Diagnosis of urothelial cancer

ABSTRACT

The present invention provides a method and a solid state device for identifying the presence of urothelial cancer in a patient comprising assigning the subject to a sub-population according to smoking habits, measuring the level of each biomarker of a panel of biomarkers in one or more samples obtained from the subject; and correlating the measured levels of the panel of biomarkers with the likelihood of the subject having urothelial cancer such that the subject can be classified as having urothelial cancer or as being a control.

CROSS REFERENCE TO RELATED APPLICATION

This application is a U.S. National Stage Application filed under 35U.S.C. § 371 and claims priority to International Application No.PCT/GB2015/051053, filed Apr. 2, 2015, which application claims priorityto Great Britain Application Nos. 1406399.4, filed Apr. 9, 2014 and1406178.2 filed Apr. 4, 2014, the disclosures of which are incorporatedherein by reference in their entireties.

FIELD OF INVENTION

The invention relates to methods for identification of biomarker panelsfor diagnosis of urothelial cancer and improved methods for diagnosingand identifying the likelihood of developing urothelial cancer.

BACKGROUND OF THE INVENTION

Urothelial cancer (UC) or bladder cancer is a leading cause of deathworldwide. Most of the patients who present with superficial UC tumourswill experience a recurrence within 5 years and almost 90% of thesepatients will have a recurrence within 15 years.

Haematuria, which refers to the presence of blood in urine, is apresenting symptom for a variety of diseases, including UC. The numberof patients presenting with haematuria is progressively increasing inour aging population and the diagnosis of serious diseases in some ofthese patients can be delayed when triage is ineffective. Therefore newrisk stratification approaches are needed.

Diagnosis of the underlying cause of hematuria is a significanthealthcare challenge. Hematuria can indicate the presence of UC, but itis also a symptom of a wide range of other pathologies includingurolithiasis, benign prostate enlargement (BPE), renal disease and otherurinary tract cancers. The final diagnosis for haematuria patientsranges from no diagnosis, through benign conditions including urinaryinfection, stone disease, BPE to renal diseases and malignant causes. UCis the most common malignancy in haematuric patients and is the fourthmost common cancer in men. UC was the estimated cause of death in150,200 people, worldwide in 2008.

UC is associated with many risk factors, for example its development isthree times more common in men than in women. However, this genderdisparity is largely historical and is related to smoking habits.Smoking increases the risk of UC four-fold and cessation of smoking isassociated with a decreased risk. Although UC is associated with smokingand carcinogen exposure, urothelial cancers that arise following chronicinflammation are usually squamous cell carcinomas.

At the time of diagnosis, approximately 70% of patients diagnosed withUC have tumours that are pathologically staged as pTa, pT1 or carcinomain situ (CIS) i.e., non-muscle invasive (NMI) disease and these patientscan have a good prognosis. When a patient's tumour is pathologicallydefined as ≥T1G3 UC, the patient is deemed to have a high risk ofprogression to a more life threatening disease. Muscle invasive UC (MIUC) encompasses all pathological stages≥pT2. The risk parameters thatare currently used to tailor follow-up for patients diagnosed with UC,include pathological parameters i.e., grade, stage and associated CIS,together with resistance to Bacille Calmette-Guerin treatment. However,it is not always possible to correctly predict the outcome for patients.This is largely attributable to the molecular heterogeneity withintumours which means that a spectrum of outcomes, spanning fromnegligible risk to life threatening prognosis, exists within the samepathologically classified groups. For this reason, all patients with NMIdisease have frequent surveillance cystoscopies and those with MI haveradiological surveillance for lymph node recurrence or distantmetastasis.

Cystoscopy is the gold standard for the detection and surveillance ofNMI UC. However, this procedure is costly for health services andinvasive for the patient. Furthermore, it requires a significantclinical input and has its own shortcomings. Cytology, anotherdiagnostic test for urothelial cancer, detects the presence of malignantcells in urine. Although cytology has high specificity, it hasinsufficient sensitivity to stand alone as a diagnostic test for UC inpatients presenting with haematuria. Despite their approval by the Foodand Drug Administration (FDA), three diagnostic urothelial cancerbiomarkers, Nuclear Matrix Protein 22, Bladder Tumour Antigen (BTA) andFibrinogen Degradation Product, are not in use in routine practise asdiagnostic biomarkers for UC because of their limited specificity. Thereis therefore a strong clinical need for tests which can at leaststratify risk of UC, and if possible, be diagnostic in haematuricpatients.

Researchers often combine multiple tests, genes or biomarkers. However,it is not possible to intuitively predict how multiple measurements,will collectively reflect the underlying biological heterogeneity incomplex diseases, such as UC. Complex diseases consist of multiplecomponents which interact to produce emergent properties that theindividual components do not possess.

Smoking and occupational carcinogen exposure are risk factors inapproximately 60% of UCs; other known risk factors include increasedage, male gender, recurrent urinary infections and bladder stones.However, the factors which confound diagnosis of UC and thecharacteristics of incorrectly classified patients have not beensystematically investigated. Identification of patient characteristicsassociated with misclassification or misdiagnosis can be useful becausethis information allows meaningful application of diagnostic classifiersfor risk stratification.

Therefore, there is a need for new approaches to identifying factorsthat confound diagnosis of serious disease. Identification of suchfactors would enable clinicians to interpret risk classifiers alongsideother clinical information at the time of triage, in order to make moreaccurate diagnoses. In the case of patients presenting with haematuriathis would reduce the number of cystoscopies and enable prioritydiagnosis of aggressive UC and other serious diseases, resulting inimproved patient outcomes at reduced costs.

SUMMARY OF THE INVENTION

According to a first aspect, the present invention provides a method ofidentifying a panel of biomarkers for diagnosis of serious disease, themethod comprising the steps of: measuring the level of each biomarker ina biomarker panel in a sample obtained from each subject in a testpopulation; stratifying the test population into sub-populations definedby variables that individually divide the test population into groupscontaining at least 35% of the total test population; and assessingcombinations of biomarkers that allow accurate classification of diseasein subjects in the sub-populations of the test population.

According to a second aspect, the present invention provides a method ofclassifying the urothelial cancer status of a subject, comprising thesteps of: assigning the subject to a sub-population according to one ormore factors selected from smoking habits, age, gender, alcoholconsumption, anti-cholesterol medication, anti-hypertensive medication,occupational risks, exposure to hazardous chemicals, cytologicaldetection of inflammatory cells and measurable urinary dipstick protein;measuring the level of each biomarker of a panel of biomarkers in one ormore samples obtained from the subject; and correlating the measuredlevels of the panel of biomarkers with the likelihood of the subjecthaving urothelial cancer such that the subject can be classified ashaving urothelial cancer or as being a control.

According to further aspects of the invention, a solid state deviceaccording to the second aspect can be used to define the likelihood of asubject having urothelial cancer or to stratify the risk of a subjecthaving a serious underlying pathology, wherein combination of antibodiespresent on the solid state device are selected according to asub-population group that is appropriate to the subject. Thesub-population group is selected according to one or more factorsselected from smoking habits, age, gender, alcohol consumption,anti-cholesterol medication, anti-hypertensive medication, occupationalrisks, exposure to hazardous chemicals, cytological detection ofinflammatory cells and measurable urinary dipstick protein.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows implementation of the supervised patient classificationanalysis. For each training data set a random forest UC classifier wasgenerated using all biomarker measurements (Table 3) and subsequentlyvalidated using the corresponding test dataset. Hypergeometric testingwas then used to determine the probabilities that each patient wascorrectly, incorrectly or inconsistently classified.

FIG. 2 shows UC diagnostic classifiers for stratified patientsubpopulations. We performed an exhaustive search to identify sets offour biomarkers that accurately classified stratified patientsubpopulations. A) Boxplots illustrating the medians and interquartilerange of the 10 top-ranked UC diagnostic classifiers for each stratifiedpatient subpopulation. B) The number of UCs and control patients in eachpatient subpopulation. C) A map illustrating the links between theenriched biomarkers of the 50 top-ranked UC diagnostic classifiers foreach stratified patient subpopulation. Yellow circles (urinebiomarkers); pink (serum biomarkers); green (plasma biomarkers). AC,anti-cholesterol; CI, cytology inflammation; AH, anti-hypertensives.

FIG. 3 shows comparative characteristics across classifiable andnon-classifiable patient subpopulations. We performed Fisher's exacttest to identify confounding variables, i.e., variables with significantheterogeneity across classifiable and non-classifiable patientgroupings. In this figure the inconsistently classified patients (n=10)are included with the non-classifiable patients (n=46). Theheterogeneity is reflected in the pie charts which demonstrate thenumbers of patients in each category within each relevant subpopulation.A) Control patients misclassified as UC were more likely to be dipstickpositive for white blood cells (wbc) (p=0.002), to have cytologyinflammation (CI) (p=0.017), abnormal cytology (p=0.019); visiblehematuria (p=0.019), proteinuria (p=0.019), to be >65 years old(p=0.028), to have high risk final diagnoses (p=0.028), and to have ahistory of benign prostate enlargement (bpehx) (p=0.036) thanclassifiable controls. B) UC patients misclassified as controls tendedto have less severe hematuria (p<0.001), to have proteinuria (p=0.002),non-muscle invasive tumors (p=0.004), stage pTa UC (p=0.005), to have noevidence of malignancy in cytology preparations (p=0.009), to be lowergrade UC (p=0.017), and to have an absence of inflammatory cells incytology preparations (CI) (p=0.017) when compared to classifiablecontrols. C) When classifiable controls were compared withnon-classifiable UC patients, non-classifiable UC patients had greaterproportions of patients who had smoked for >10 years (p=0.001); greaterproportions of patients taking AH medication (p=0.001); greaterproportions of patients taking beta blockers (p=0.004), and greaterproportions of patients who were smokers (p=0.019). Variables in A, Band C are illustrated in decreasing order of significance from left toright. p-values were adjusted by false discovery rate (FDR); α<0.05. wbcdipstick white blood cells; CI cytology inflammation; bpehx history ofbenign prostate enlargement; AH anti-hypertensive medication; betablbeta blocker medication.

FIG. 4 shows characteristics of the patients classified as controls andpatients classified as urothelial cancers. Patients with hematuria wereclassified into urothelial cancers (UC) or controls (CTL) using abiochip [14] formatted with the antibodies against the proteins of a UCdiagnostic classifier for all patients. A) Patients classified as UCwere predominantly high grade/stage UCs or controls (CTL), a proportionof whom may had serious diagnoses. B) Patients classified as controlsincluded 21 patients with pTa tumors, one with a pT1 tumor and one whohad carcinoma in situ. Twenty-two of these 23 patients with transitionalcell carcinoma of the bladder (TCCB) were either smokers or aged>65years. The 18 patients classified as controls who did not smoke and wereaged 65 years were low risk. TCC=transitional cell carcinoma, BPE=benignprostate enlargement, RCC=renal cell carcinoma, UTI=urinary tractinfection.

DESCRIPTION OF THE INVENTION

The present invention provides both a method of defining biomarkerpanels useful in diagnosing a serious disease such as urothelial cancerand methods of diagnosing urothelial cancer and identifying thelikelihood of developing urothelial cancer. The methods provided areadvantageous as they provide clinicians with information concerning riskfactors that confound traditional diagnostic methods and that can beused at the time of triage. Using the method of the invention, eachpatient can be assigned to a relevant sub-population so that appropriatetesting can be carried out so as to permit accurate diagnosis andpatient classification. As a result, patients can be followed up moreeffectively, further investigational and therapeutic intervention can bedirected more appropriately, and resources in the healthcare system canbe better managed. Furthermore, the invention enables priority diagnosisof aggressive urothelial cancer and other serious diseases, leading toimproved patient outcomes at reduced costs.

The method of identifying a panel of biomarkers for diagnosis of seriousdisease involves three steps: a first ‘data gathering’ step thatinvolves measurement of biomarker levels in samples obtained fromsubjects in a test population; a second ‘population stratification’ stepthat involves subdividing the test population according to risk factorsthat are under investigation; and a third ‘classification’ step thatinvolves identification of biomarkers and panels of biomarkers thatpermit accurate identification of the disease within subdivided sectionsof the test population from the ‘population stratification’ step.

The first ‘data gathering’ step involves measurement of a panel ofbiomarker candidates in samples from subjects in the test population.The panel of biomarker candidates should include those biomarkers thatare being investigated for usefulness in diagnosing the disease, and inthe case of urothelial cancer this panel includes Bladder Tumour Antigen(BTA), Carcino-embryonic antigen (CEA), Human cytokeratin 18 (CK18),C-reactive protein (CRP), Creatinine, d Dimer, Epidermal growth factor(EGF), FAS, Hyaluronidase (HA), IL1α, IL1β, IL2, IL4, IL6, IL8, IL10,Interferon gamma (IFNγ), Monocyte Chemoattractant Protein 1 (MCP1),matrix metalloproteinase 9 (MMP9), Neutrophil gelatinase-associatedlipocalin (NGAL), MMP9NGAL complex MMP9NGAL), Neuron specific enolase(NSE), Free Prostate Specific Antigen (FPSA), Total Prostate SpecificAntigen (TPSA), Thrombomodulin (TM), Tumour necrosis factor α (TNFα),sTNFR1, sTNFR2, Vascular endothelial growth factor (VEGF) and vonWillebrand factor (vWF). The test population for this method shouldinclude subjects suffering from the disease being investigated andsubjects not suffering form that disease, and the disease status of eachsubject in the test population should be confirmed or be able to beconfirmed independently of the method of the invention.

The second ‘population stratification’ step of the method involvessubdividing the test population based on the presence or absence ofknown disease risk factors or other factors that are known to confounddiagnosis of the disease using known biomarkers. In the case ofurothelial cancer such factors include history of smoking, age, gender,alcohol consumption, history of anti-cholesterol medication, history ofanti-hypertensive medication, occupational exposure to hazardouschemicals, cytological detection of inflammatory cells and presence ofmeasurable dipstick protein in urine. Subdivision of the total testpopulation according to each of these factors should yield two groups ofsubjects, and each group should comprise no less than 33% of the totaltest population.

The third ‘classification’ step of the method involves association ofmeasured levels of individual biomarkers or panels of biomarkers withthe correct classification of subjects within a subpopulation assuffering from or nor suffering from the disease being investigated. Foreach subpopulation an exhaustive search of sets of biomarkers isconducted, using a logistic regression classification to definediagnostic sets of biomarkers. The performance of each set of biomarkerswas assessed using the average Area Under the Curve (AUC) measure andstandard deviation (sd) from a repeated random sub-sampling analyses.Top performing sets of biomarkers are then identified on the basis oftheir hypergeometric distribution:

$\begin{matrix}{{P\left( {x = a} \right)} = \frac{\begin{pmatrix}k \\a\end{pmatrix}\begin{pmatrix}{N - k} \\b\end{pmatrix}}{\begin{pmatrix}N \\m\end{pmatrix}}} & (1)\end{matrix}$

For the stratified analysis the variable “a” denotes the count frequencyof a biomarker i being present among the top-ranked 50 sets ofbiomarkers and “b” in the remaining sets of biomarkers. “m” is the totalcount frequency of a biomarker i among all sets of biomarkers. “k”denotes the total count frequency of all biomarkers in the 50 top-rankedsets of biomarkers. “N” denotes the total count frequency of allbiomarkers among all sets of biomarkers.

The method of diagnosing urothelial cancer in a subject involves threesteps: a first ‘assigning’ step that involves identification of factorspresent in the subject that are likely to confound diagnosis ofurothelial cancer using available biomarkers; a second ‘data gathering’step that involves measuring the level of the appropriate panel ofbiomarkers in one or more samples obtained from the subject; and a third‘correlating’ step that involves classification of the subject assuffering from or not suffering from urothelial cancer based on theconfounding factors identified and the measured levels of the panel ofbiomarkers.

In the context of the present invention the term “urothelial cancer” isunderstood to include urothelial carcinoma (UC), bladder squamous cellcarcinoma or bladder adenocarcinoma. Preferably, the urothelial canceris urothelial carcinoma.

The terms “diagnose” and “diagnosing” as used herein relate to theconfirmation that a subject is suffering or is likely to suffer fromthat disease. The terms “classify” and “classifier” as used hereinrelate to classification of a subject as suffering from (or likely tosuffer from) or not suffering from (or not likely to suffer from) aspecified disease such as urothelial cancer.

The terms “subject” and “patient” are used interchangeably herein andrefer to a mammal including a non-primate (e.g. a cow, pig, horse, dog,cat, rat and mouse) and a primate (e.g. a monkey and human). Preferablythe subject or patient is a human.

Preferably, the subject is a patient a presenting with haematuria. Forthe avoidance of doubt, the term “haematuria” refers to the presence ofred blood cells in the urine. Haematuria may be caused by a number ofconditions, such as urothelial cancer, BPE, kidney stones and infection,prostate cancer, renal cell carcinoma or urinary tract infections.

Preferably, the biomarkers are detected in at least one sample obtainedfrom the subject selected from a urine sample, blood sample, serumsample or plasma sample.

The terms “serious disease” and “serious underlying pathology” are usedinterchangeably herein, and refer to life-threatening conditions such askidney disease, aggressive bladder cancer or other aggressive cancers.

The term “has a history of smoking” refers herein to whether or not thesubject smokes or has smoked. The term “smoking” includes all forms oftobacco smoking, including cigarettes, cigars and pipe tobacco. Anindividual subject is either classified as positive (i.e. has a historyof smoking) or negative (i.e. no history of smoking) for smoking habits.

The term “gender” refers to whether the subject is male or female.

The phrases “history of prescribed anti-hypertensive medication” and“history of anti-cholesterol medication” refers herein to whether or notthe subject is prescribed, or has a history of being prescribed, one ormore of these medications. For the purpose of the method of theinvention, medication is considered separately. Therefore an individualsubject could be positive for one or more medication but negative forthe other. For the avoidance of doubt, anti-hypertensives are a class ofdrugs used to treat hypertension (high blood pressure). The most widelyused include thiazide diuretics, ACE inhibitors, calcium channelblockers, beta-blockers, and angiotensin II receptor antagonists orARBs. Anti-cholesterol medications are a class of drugs that reduce thelevel of circulating low density lipoprotein cholesterol, reduce thelevel of circulating triglycerides and/or increase the level ofcirculating high density lipoprotein cholesterol. These drugs includeStatins, Bile acid binding resins and agents, Cholesterol absorptioninhibitors, Combination cholesterol absorption inhibitor and statin,Fibrates, Niacin, Combination statin and niacin, and Omega-3 fattyacids.

The phrase “history of alcohol consumption” refers herein to whether ornot the subject consumes or has consumed alcohol including all forms ofalcohol, including spirits, wine and beer. An individual subject iseither classified as positive (i.e. has a history of consuming alcohol)or negative (i.e. no history of consuming alcohol).

The phrase “history of exposure to occupational risks or hazardouschemicals” refers herein to whether or not the subject is known to havebeen exposed to known occupational risks or hazardous chemicals. Eachsubject's occupational risk score can be classified and scored as low,moderate or high. An individual subject is either classified as positive(i.e. has a history of exposure to occupational risks or hazardouschemicals) if this factor is scored as moderate or high, or classifiedas negative (i.e. no history of exposure to occupational risks orhazardous chemicals) if this factor is scored as low.

The term “proteinuria” refers herein to whether or not a urine sampleobtained from a subject contains an abnormal level of protein asmeasured using a standard “dipstick” assay. Levels of urinary proteinless than 30 mg/dL are considered normal, while levels above thatconcentration are detectable by the dipstick test and constituteproteinuria. An individual subject is either classified as positive(i.e. has proteinuria) if protein is detected by the dipstick test, orclassified as negative (i.e. does not have proteinuria) if no protein isdetected by the dipstick test.

The phrase “cytological detection of inflammatory cells” refers hereinto whether or not a sample obtained from the subject subjected tocytological examination provides evidence of the presence ofinflammatory cells. An individual subject is either classified aspositive (i.e. has cytological detection of inflammatory cells) ifinflammatory cells are detectable on cytology examination, or classifiedas negative (i.e. does not have cytological detection of inflammatorycells) if no inflammatory cells are detectable on cytology examination.

The word “history” is sometimes abbreviated herein to “Hx”.

The biomarkers are selected from the list comprising: Bladder TumourAntigen (BTA), Carcino-embryonic antigen (CEA), Human cytokeratin 18(CK18), C-reactive protein (CRP), Creatinine, d Dimer, Epidermal growthfactor (EGF), FAS, Hyaluronidase (HA), IL1α, IL1β, IL2, IL4, IL6, IL8,IL10, Interferon gamma (IFNγ), Monocyte Chemoattractant Protein 1(MCP1), matrix metalloproteinase 9 (MMP9), Neutrophilgelatinase-associated lipocalin (NGAL), MMP9NGAL complex (MMP9NGAL),Neuron specific enolase (NSE), Free Prostate Specific Antigen (FPSA),Total Prostate Specific Antigen (TPSA), Thrombomodulin (TM), Tumournecrosis factor α (TNFα), sTNFR1, sTNFR2, Vascular endothelial growthfactor (VEGF) and von Willebrand factor (vWF).

Diagnosis may be made on the basis of the level of expression of thebiomarker in the patient. The biomarker combinations of the presentinvention are preferably those which are expressed in the urine of apatient. Particular biomarkers may be expressed in the patient's blood.

The level of expression of the biomarker combination in the patient isdetected in one or more samples that are isolated from the patient. In apreferred embodiment, the sample isolated from the patient is a urinesample or a blood sample.

Concentrations or expression levels of the biomarkers within thecombination may be determined either sequentially or simultaneously inone or more samples isolated from the patient. The biomarkerconcentrations within the isolated sample may be determined by routinemethods, which are known in the art.

In the method of the present invention an individual biomarker withinthe combination of biomarkers tested may be found at a different levelor a similar level compared to the corresponding biomarker in a normalcontrol sample. In some embodiments, the concentration of biomarkers arefound at a significantly higher level than in a control sample. Thedetermination of a “higher concentration” and a “lower concentration” isrelative and determined with respect to a control subject known not tohave cancer, preferably bladder cancer. Significant levels of biomarkerswill be apparent to the skilled person.

Osmolarity, total urinary protein (TUP) and/or creatinine levels in thesample may also be measured and the resulting value(s) included in thestatistical analysis. Creatinine levels (μmol/L) can be measured using aDaytona RX Series Clinical Analyser (Randox). Osmolarity (mOsm) can bemeasured using a Löser Micro-Osmometer (Type 15) (Löser Messtechnik,Germany). TUP levels (mg/ml) can be measured in a urine sample byBradford assay A₅₉₅ nm (Hitachi U2800 spectrophotometer) using bovineserum albumin as the standard.

If the subject has a history of smoking the levels of urinary EGF,urinary IL6, urinary VEGF and urinary CK18; urinary EGF, serum IL8,urinary vWF and urinary FAS; or urinary EGF, urinary IL1α, plasmaMMP9NGAL and urinary vWF are measured.

If the subject has a history of smoking the levels of EGF, IL1β, sTNFR,VEGF and CK18; BTA, EGF, IL1β, vWF and FAS; EGF, IL1β, IL8, TM, and vWF;dDimer, EGF, IL1β, IL8, VEGF and vWF; EGF, IL1β, NSE, sTNFR2, VEGF andvWF; EGF, IL2, TM, sTNFR2, VEGF and CK18; EGF, IL1α, MMP9, MMP9NGAL,NSE, VEGF and vWF; EGF, IL1β, NGAL, NSE, sTNFR1, VEGF and vWF; ordDimer, EGF, IL1α, IL8, NSE, vWF and FAS are measured in a urine sampleobtained from the subject.

If the subject has a history of smoking the levels of d-Dimer, EGF,IL1α, IL8 and NGAL; IL1α, IL2, IL8, NGAL and sTNFR1; IL1α, IL10, NGAL,NSE and TNϕα; d-Dimer, IL2, IL10, MMP9NGAL, NGAL and sTNFR1; EGF, FPSA,IL10, NGAL, TNFα and TPSA; CEA, IL1α, IL4, IL8, IL10 and NGAL; EGF, CRP,IL10, MMP9NGAL, NGAL, TM and VEGF; CEA, CRP, IL10, MMP9NGAL, NGAL, TMand TNFα; or CEA, d-Dimer, IL2, IL8, IL10, IFNγ and NSE are measured ina serum sample obtained from the subject.

If the subject has a history of smoking the levels of IL4, IFNγ, MCP1,MMP9NGAL and TM; IL1α, IL4, IFNγ, MCP1 and MMP9NGAL; EGF, IL1α, IL4,MCP1, MMP9NGAL; d-Dimer, IL1α, IL4, IL10, MMP9NGAL and sTNFR1; IL4,IL10, MMP9NGAL, TM, sTNFR1 and TNFα; IL1β, IL4, IL8, MCP1, MMP9NGAL andTNFα; IL1α, IL1β, IL2, IL4, IL10, MMP9NGAL and TNFα; d-Dimer, IL1α, IL4,IFNγ, MCP1, MMP9NGAL and TM; or d-Dimer, EGF, IL1α, IL4, IL10, IFNγ, andMMP9NGAL are measured in a plasma sample obtained from the subject.

If the subject does not have a history of smoking the levels of serumCEA, urinary EGF, plasma IL8 and urinary CK18; serum CEA, plasma IL8,serum NGAL and serum TM; or serum CEA, plasma IL8, serum NGAL and plasmaNSE are measured.

If the subject does not have a history of smoking the levels of BTA,MMP9NGAL, TM, sTNFR2 and VEGF; BTA, IL4, MMP9, NSE and FAS; BTA,MMP9NGAL, TNFα, sTNFR2 and VEGF; BTA, MCP1, MMP9, sTNFR2, vWF and FAS;d-Dimer, IL6, IL8, NGAL, NSE and TNFα; BTA, IL6, MCP1, TNFα, sTNFR2 andFAS; EGF, CRP, IL8, NGAL, NSE, TM and HA; BTA, EGF, IL8, MCP1, NGAL,NSE, sTNFR1; or BTA, IL4, MCP1, TM, sTNFR2, vWF and FAS are measured ina urine sample obtained from the subject.

If the subject does not have a history of smoking the levels of CEA,EGF, IL4, NGAL and TNFα; CEA, EGF, IL8, NGAL and TPSA; CEA, IL8, MCP1,NGAL and TPSA; CEA, IL6, IL8, MMP9NGAL, NGAL and VEGF; CEA, d-Dimer,CRP, MMP9NGAL, NGAL and NSE; CEA, CRP, IL2, MMP9NGAL, NGAL and TM; CEA,EGF, CRP, IL4, IL8, NGAL and NSE; CEA, IL6, IL8, IFNγ, NGAL, TM andVEGF; or CEA, FPSA, CRP, IL4, MMP9NGAL, NGAL and TM are measured in aserum sample obtained from the subject.

If the subject does not have a history of smoking the levels of IL1α,MMP9NGAL, NSE, sTNFR1 and VEGF; IFNγ, MCP1, MMP9NGAL, NGAL and NSE;IFNγ, MMP9NGAL, NGAL, NSE and TNFα; IL6, IFNγ, MMP9NGAL, NGAL, NSE andTNFα; d-Dimer, IL1α, IL4, MMP9NGAL, NSE and VEGF; d-Dimer, EGF, IL1α,IL8, MMP9NGA and NSE; d-Dimer, EGF, IL1α, IFNγ, MMP9NGAL, TNFα and VEGF;EGF, IL1α, IL2, MMP9NGAL, NGAL, NSE and TM; or IL1α, IFNγ, MMP9NGAL,NGAL, NSE, TM and TNFα are measured in a plasma sample obtained from thesubject.

If the subject is aged 65 years or older the levels of serum IL2, serumMMP9NGAL, serum NGAL and plasma sTNFR1; urinary MMP9NGAL, serum NGAL,plasma NGAL and urinary vWF; or serum CEA, serum d-Dimer, plasma d-Dimerand serum IFN-J are measured.

If the subject is aged 65 years or older the levels of BTA, IL1β, VEGF,vWF and HA; d-Dimer, IL1α, NSE, vWF and HA; BTA, d-Dimer, IL1β, vWF andHA; BTA, IL1β, IL4, VEGF, vWF and HA; BTA, IL1β, IL8, sTNFR2, vWF andHA; BTA, EGF, IL1α, NSE, vWF and HA; d-Dimer, CRP, IL1α, IL2, NSE, vWFand HA; BTA, IL1α, IL8, MMP9NGAL, vWF, HA and CK18; or d-Dimer, IL1α,MCP1, NSE, TNFα, vWF and HA are measured in a urine sample obtained fromthe subject.

If the subject is aged 65 years or older the levels of CEA, d-Dimer,IL4, NGAL and TM; IL1α, MMP9NGAL, NGAL, sTNFR1 and TNFα; IL2, MMP9NGAL,NGAL, sTNFR1 and VEGF; CEA, d-Dimer, IL1α, NGAL, NSE and TM; CEA, EGF,IL1α, MMP9NGAL, NGAL and TPSA; CEA, d-Dimer, CRP, IL1β, NGAL and TM;CEA, d-Dimer, FPSA, CRP, IL10, NGAL and TM; CEA, d-Dimer, CRP, NGAL,NSE, TM and TPSA; or d-Dimer, IL1α, IL8, IFNγ, MMP9NGAL, NGAL and TM aremeasured in a serum sample obtained from the subject.

If the subject is aged 65 years or older the levels of CRP, IL1α,MMP9NGAL, TM and VEGF; CRP, IL1α, IL1β, MMP9NGAL and NGAL; CRP, IL1α,IL4, MMP9NGAL and TM; CRP, IL1α, IL2, IL4, MMP9NGAL and TM; EGF, CRP,IL1α, IL1β, MMP9NGAL and VEGF; EGF, IL1α, IL6, MMP9NGAL, TM and TNFα;CRP, IL1α, IL10, MMP9NGAL, TM, TNFα and VEGF; IL1α, IL6, IL10, MMP9NGAL,TM, TNFα and VEGF; or CRP, IL1α, IL4, IL6, MMP9NGAL, TM and TNFα aremeasured in a plasma sample obtained from the subject.

If the subject is aged less than 65 years old the levels of serum CEA,urinary EGF, serum IL1α, and urinary VEGF; serum CEA, urinary CRP, serumIL1α and urinary VEGF; or serum CEA, serum-IL1α, plasma IFNγ and urinaryVEGF are measured.

If the subject is aged less than 65 years old the levels of EGF, IL2,HA, FAS and CK18; EGF, IL2, MMP9NGAL, HA and CK18; EGF, vWF, HA, FAS andCK18; EGF, IL2, IL8, MMP9, HA and CK18; BTA, EGF, IL1β, IL8, HA andCK18; d-Dimer, EGF, NSE, vWF, HA and CK18; EGF, CRP, IL1β, IL2, IL8, HAand CK18; EGF, IL1β, IL4, IL8, vWF, HA and CK18; or EGF, IL1β, IL6, IL8,MMP9, HA and CK18 are measured in a urine sample obtained from thesubject.

If the subject is aged less than 65 years old the levels of CEA, IL1α,IL4, TM and TNFα; CEA, IL1α, IL2, IL4 and IL8; CEA, IL1α, IL1β, IL4 andVEGF; CEA, IL1α, IL4, IL8, MMP9NGAL and sTNFR1; CEA, IL1α, IL2, IL4, NSEand sTNFR1; CEA, EGF, IL1α, IL4, IL8 and TM; CEA, IL1α, IL2, IL4, IL8,IFNγ and MMP9NGAL; CEA, EGF, FPSA, IL1α, IL4, IL8 and VEGF; and CEA,IL1α, IL2, IL8, IFNγ, MCP1 and sTNFR1 are measured in a serum sampleobtained from the subject.

If the subject is aged less than 65 years old the levels of d-Dimer,IL8, IL10, NSE and VEGF; d-Dimer, IL8, MMP9NGAL, TNFα and VEGF; EGF,IL8, IL10, MMP9NGAL and sTNFR1; EGF, CRP, IL6, IL8, IL10 and sTNFR1;CRP, IL6, IL8, IL10, IFNγ and sTNFR1; d-Dimer, IL4, IL8, MMP9NGAL, NGALand TNFα; CRP, IL4, IL6, IL8, IL10, MMP9NGAL and TNFα; EGF, CRP, IL1β,IL8, IFNγ, NGAL and sTNFR1; or d-Dimer, EGF, CRP, IL8, IL10, IFNγ andMMP9NGAL are measured in a plasma sample obtained from the subject.

If the subject has a history of anti-hypertensive medication the levelsof urinary EGF, urinary IL1α, serum IL10 and urinary vWF; urinary EGF,plasma IL10, urinary VEGF and urinary vWF; or serum sTNFR1, plasmasTNFR1, serum TNFα and urinary vWF are measured.

If the subject has a history of anti-hypertensive medication the levelsof CRP, IL2, IL8, sTNFR2 and vWF; EGF, IL8, NSE, TNFα and vWF; BTA, EGF,IL4, vWF and HA; BTA, EGF, IL1β, IL8, VEGF and vWF; d-Dimer, CRP, IL8,sTNFR2, vWF and CK18; d-Dimer, EGF, IL2, VEGF, vWF and FAS; CRP, IL1β,IL6, IL8, MMP9, NGAL and vWF; d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 andvWF; or BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF are measured in aurine sample obtained from the subject.

If the subject has a history of anti-hypertensive medication the levelsof CEA, NGAL, NSE, TNFα and TPSA; CEA, MMP9NGAL, NGAL, TM and TNFα; CEA,IL1β, NGAL, sTNFR1 and TPSA; CEA, IL1β, IL10, NGAL, TM and VEGF; CEA,d-Dimer, IL1β, MMP9NGAL, NGAL and TM; CEA, EGF, IL1α, IL1β, NGAL andTNFα; CEA, IL1α, IL1β, IL10, NGAL, sTNFR1 and TNFα; CEA, IL1α, NGAL,NSE, TM, TNFα and TPSA; or CEA, IL1β, IL4, IL10, MMP9NGAL, NGAL and TMare measured in a serum sample obtained from the subject.

If the subject has a history of anti-hypertensive medication the levelsof IL1α, IL1β, IL4, IFNγ and VEGF; EGF, CRP, IL2, IL4 and IL8; EGF, CRP,IL2, IL10 and NGAL; EGF, IL6, IL10, IFNγ, MCP1 and MMP9NGAL; d-Dimer,EGF, IL1β, IL4, IL6 and MCP1; EGF, CRP, IL1β, IL2, MMP9NGAL and NGAL;d-Dimer, EGF, CRP, IL2, IL10, MMP9NGAL and TM; CRP, IL1α, IL1β, IL4,IL6, IFNγ and sTNFR1; or EGF, CRP, IL4, IL6, IL10, IFNγ and MMP9NGAL aremeasured in a plasma sample obtained from the subject.

If the subject does not have a history of anti-hypertensive medicationthe levels of serum CEA, urinary CRP, urinary NSE and serum TNFα; serumCEA, urinary CRP, serum IL4 and urinary sTNFR1; or urinary Creatinine,serum IL6, plasma MMP9NGAL and urinary VEGF are measured.

If the subject does not have a history of anti-hypertensive medicationthe levels of CRP, NGAL, VEGF, HA and CK18; d-Dimer, TNFα, VEGF, HA andCK18; MMP9, NSE, TM, VEGF and FAS; EGF, NGAL, VEGF, vWF, HA and CK18;CRP, IL1β, IL6, sTNFR1, VEGF and vWF; d-Dimer, EGF, IL4, VEGF, HA andCK18; CRP, IL1β, IL6, IL8, MMP9, NGAL and vWF; d-Dimer, IL8, MMP9, NSE,TM, sTNFR2 and vWF; or BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF aremeasured in a urine sample obtained from the subject.

If the subject does not have a history of anti-hypertensive medicationthe levels of CEA, d-Dimer, IL4, MMP9NGAL and sTNFR1; CEA, EGF, IL10,MMP9NGAL and TNFα; CEA, d-Dimer, CRP, IL4 and IL10; CEA, d-Dimer, CRP,IL4, IL10 and TM; CEA, d-Dimer, CRP, IL4, IL6 and MMP9NGAL; CEA,d-Dimer, IL2, IL4, IL8 and MMP9NGAL; CEA, d-Dimer, EGF, IL4, IL8, IL10and NSE; CEA, d-Dimer, CRP, IL4, MCP1, MMP9NGAL and TNFα; and CEA,d-Dimer, CRP, IL4, IL6, TM and TNFα are measured in a serum sampleobtained from the subject.

If the subject does not have a history of anti-hypertensive medicationthe levels of EGF, IL1α, IL8, MMP9NGAL and VEGF; IL1α, IL8, IFNγ,MMP9NGAL and VEGF; CRP, IL1α, IL8, MMP9NGAL and NGAL; EGF, CRP, IL1β,IL8, MMP9NGAL and VEGF; CRP, IL1α, IL6, IL8, IL10, MMP9NGAL; EGF, IL1β,IL4, IL8, MMP9NGAL and VEGF; EGF, CRP, IL1α, IL8, MMP9NGAL, TNFα andVEGF; EGF, CRP, IL1β, IL8, MMP9NGAL, sTNFR1 and VEGF; and d-Dimer, EGF,IL1β, IL6, IL8, MMP9NGAL and VEGF are measured in a plasma sampleobtained from the subject.

If the subject has cytological detection of inflammatory cells thelevels of urinary BTA, serum CEA, plasma IL10 and urinary CK18; urinaryBTA, plasma IL6, serum NSE and plasma NSE; or urinary dipstick protein,urinary BTA, plasma IL6 and serum NGAL are measured.

If the subject has cytological detection of inflammatory cells thelevels of BTA, IL1α, NGAL, sTNFR1 and vWF; BTA, IL8, MMP9NGAL, VEGF andCK18; BTA, IL6, MMP9NGAL, NSE and CK18; BTA, IL2, MMP9NGAL, sTNFR1, TNFαand VEGF; BTA, IL2, MMP9NGAL, NGAL, TNFα and CK18; BTA, IL2, MMP9NGAL,NSE, VEGF and CK18; BTA, IL2, MMP9NGAL, NGAL, sTNFR1, TNFα and VEGF;BTA, IL2, MMP9NGAL, TM, sTNFR1, vWF and FAS; or BTA, IL2, MMP9NGAL,sTNFR1, VEGF, vWF and CK18 are measured in a urine sample obtained fromthe subject.

If the subject has cytological detection of inflammatory cells thelevels of CEA, IL1α, NGAL, NSE and TPSA; IL1α, MMP9NGAL, NGAL, TPSA andVEGF; CEA, IL1α, IL10, NGAL and VEGF; CEA, IL10, MMP9NGAL, NGAL, TNFαand VEGF; IL1α, IL10, MMP9NGAL, NGAL, NSE and VEGF; CRP, IL10, MMP9NGAL,NGAL, TPSA and VEGF; CEA, CRP, IL1β, IL2, TM, sTNFR1 and TPSA; CRP,IL1β, IL2, IL6, MMP9NGAL, NGAL and TNFα; or CRP, IL1β, IL2, MMP9NGAL,NGAL, NSE and TNFα are measured in a serum sample obtained from thesubject.

If the subject has cytological detection of inflammatory cells thelevels of IL1α, IL6, IL8, MMP9NGAL and NSE; IL6, IFNγ, MMP9NGAL, NSE andsTNFR1; IL1α, IL1β, IL8, IL10 and MMP9NGAL; IL6, IL8, IFNγ, MMP9NGAL,NGAL and NSE; IL1α, IL6, MMP9NGAL, NSE, TM and TNFα; d-Dimer, IL4, IL8,IFNγ, MMP9NGAL and VEGF; IL1α, IL8, IL10, MCP1, MMP9NGAL, NSE and TM;d-Dimer, IL2, IL6, IL8, MMP9NGAL, TM and sTNFR1; or IL1α, IL2, IL6, IL8,MCP1, MMP9NGAL and NSE are measured in a plasma sample obtained from thesubject.

If the subject does not have cytological detection of inflammatory cellsthe levels of serum CEA, plasma IL8, serum TNFα and urinary FAS; urinaryEGF, serum EGF, serum FPSA and serum IL4; or urinary EGF, urinary CRP,urinary IL4 and urinary NSE are measured.

If the subject does not have cytological detection of inflammatory cellsthe levels of EGF, CRP, IL4, TM and vWF; BTA, d-Dimer, EGF, CRP and IL4;EGF, CRP, IL4, IL6 and vWF; d-Dimer, EGF, CRP, IL4, sTNFR1 and vWF;d-Dimer, EGF, CRP, IL4, sTNFR1 and sTNFR2; EGF, IL2, IL4, sTNFR2, VEGFand vWF; EGF, CRP, IL4, MCP1, VEGF, FAS and CK18; d-Dimer, EGF, CRP,IL4, IL6, sTNFR2 and vWF; or d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 andCK18 are measured in a urine sample obtained from the subject.

If the subject does not have cytological detection of inflammatory cellsthe levels of CEA, EGF, CRP, IL4 and IFNγ; d-Dimer, FPSA, IL6, IFNγ andNGAL; IL1α, IL4, MMP9NGAL, NGAL and TM; IL4, MMP9NGAL, NGAL, NSE, sTNFR1and TPSA; CEA, EGF, FPSA, IL4, NSE and sTNFR1; CEA, EGF, FPSA, IL4, MCP1and VEGF; FPSA, IL2, IL4, IL6, MMP9NGAL, NGAL and sTNFR1; CEA, EGF,FPSA, CRP, IL4, IL6 and MMP9NGAL; or d-Dimer, IL1β, IL4, IL8, MCP1, NGALand TM are measured in a serum sample obtained from the subject.

If the subject does not have cytological detection of inflammatory cellsthe levels of d-Dimer, IL1β, IL8, MMP9NGAL and TM; d-Dimer, IL8, TM,TNFα and VEGF; IL2, IL8, MMP9NGAL, TM and TNFα; d-Dimer, IL8, MMP9NGAL,NSE, TM and TNFα; d-Dimer, IL2, IL8, MMP9NGAL, NSE and TNFα; d-Dimer,IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα; d-Dimer, IL1α, IL8, MMP9NGAL, TM,TNFα and VEGF; d-Dimer, CRP, IL2, IL6, IL8, MMP9NGAL and TNFα; ord-Dimer, IL1α, IL1β, IL8, MMP9NGAL, TM and VEGF are measured in a plasmasample obtained from the subject.

If the subject has a history of alcohol consumption the levels ofurinary EGF, urinary IL1β, plasma MMP9NGAL and urinary vWF; serum CEA,urinary EGF, urinary vWF and urinary CK18; or serum CEA, urinary EGF,plasma NSE and urinary vWF are measured.

If the subject has a history of alcohol consumption the levels of EGF,MMP9, sTNFR2, VEGF and vWF; EGF, IL1α, IL4, vWF and FAS; EGF, IL1α,MMP9, vWF and HA; d-Dimer, EGF, CRP, IL1α, IL6 and vWF; EGF, CRP, IL1α,sTNFR, vWF and CK18; BTA, EGF, CRP, IL1α, vWF and FAS; EGF, IL1α, IL6,NGAL, sTNFR2, vWF and FAS; EGF, IL1α, IL2, IL6, NGAL, VEGF and vWF; oru-EGF, u-IL1α, u-NGAL, u-NSE, sTNFR2, u-vWF and u-CK18 are measured in aurine sample obtained from the subject.

If the subject has a history of alcohol consumption the levels of CRP,IL1β, IL6, IL8 and NGAL; d-Dimer, IL1β, IL4, IFNγ and NGAL; CRP, IL1β,IL4, MCP1 and NGAL; EGF, CRP, IL1α, IL1β, NGAL and TPSA; CEA, CRP, IL1β,IL2, NGAL and NSE; CEA, d-Dimer, CRP, IL1α, IL6 and NGAL; EGF, CRP, IL8,MCP1, MMP9NGAL, NGAL and sTNFR1; CEA, EGF, CRP, IL1β, MMP9NGAL, NGAL andTM; or CEA, d-Dimer, IL1α, IL2, IL4, IL10 and NGAL are measured in aserum sample obtained from the subject.

If the subject has a history of alcohol consumption the levels ofd-Dimer, IL4, MMP9NGAL, NSE and TM; IL1β, IL4, MMP9NGAL, NSE and TNFα;EGF, CRP, IL4, MMP9NGAL and sTNFR1; IL1α, IL2, IL4, MMP9NGAL, NSE andTNFα; IL2, IL4, IL6, MMP9NGAL, NSE and TM; CRP, IL1α, IL1β, IL4,MMP9NGAL and TNFα; d-Dimer, IL1β, IL4, MMP9NGAL, NGAL, NSE and VEGF;d-Dimer, IL1α, IL2, MMP9NGAL, NSE, sTNFR and TNFα; or d-Dimer, CRP,IL1α, IL4, IL10, NSE and sTNFR are measured in a plasma sample obtainedfrom the subject.

If the subject does not have a history of alcohol consumption the levelsof serum MMP9NGAL, serum sTNFR1, serum TNFα and urinary VEGF; serum CEA,urinary EGF, serum IL10 and serum NGAL; or urinary IL6, plasma MMP9NGAL,urinary VEGF and urinary CK18 are measured.

If the subject does not have a history of alcohol consumption the levelsof IL2, IL8, NGAL, HA and CK18; IL2, IL4, VEGF, HA and CK18; IL1β, IL2,IL8, NGAL and CK18; IL2, IL4, IL8, NGAL, HA and CK18; BTA, d-Dimer, IL2,IL8, MMP9NGAL and CK18; IL2, IL4, IL8, sTNFR2, HA and CK18; IL1β, IL2,IL6, IL8, NGAL, NSE and CK18; IL1α, IL2, IL6, IL8, NGAL, HA and CK18; orBTA, IL1α, IL2, IL8, NGAL, VEGF and CK18 are measured in a urine sampleobtained from the subject.

If the subject does not have a history of alcohol consumption the levelsof CEA, IL1α, IL8, TM and sTNFR1; CEA, IL1α, IL6, NGAL and TM; CEA,IL1α, IL2, TM and sTNFR1; CEA, IL2, IL8, NSE, TM and sTNFR1; CEA, IL10,MMP9NGAL, NSE, TM and sTNFR1; CEA, CRP, IL2, IL10, NGAL and TM; CEA,CRP, IL4, IL6, IL10, sTNFR1 and TPSA; CEA, d-Dimer, EGF, IL1α, IL10, NSEand sTNFR1; or CEA, d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1 are measuredin a serum sample obtained from the subject.

If the subject does not have a history of alcohol consumption the levelsof IL1α, IFNγ, MMP9NGAL, sTNFR1 and TNFα; EGF, IL4, MCP1, MMP9NGAL andsTNFR1; IL1α, IL8, IL10, MMP9NGAL and VEGF; IL1α, IL1β, IL10, IFNγ,MMP9NGAL and VEGF; EGF, CRP, IL1α, MMP9NGAL, TNFα and VEGF; IL1α, IL6,IL8, IFNγ, MMP9NGAL and sTNFR1; IL1α, IL2, IL8, IFNγ, MMP9NGAL, sTNFR1and TNFα; IL1α, IL2, IL6, IL10, MMP9NGAL, TNFα and VEGF; or IL1α, IL4,IL6, IL10, MMP9NGAL, NGAL and VEGF are measured in a plasma sampleobtained from the subject.

If the subject has a history of exposure to occupational risks orhazardous chemicals the levels of serum CEA, urinary EGF, urinary VEGFand urinary vWF; urinary EGF, serum IL8, urinary vWF and urinary HA; orserum IL4, plasma IL8, serum MCP1 and urinary VEGF are measured.

If the subject has a history of exposure to occupational risks orhazardous chemicals the levels of BTA, IL2, IL4, MMP9NGAL and VEGF; BTA,IL1α, IL8, NGAL and NSE; BTA, CRP, IL4, NSE and CK18; BTA, d-Dimer, CRP,IL4, sTNFR1 and vWF; IL4, IL8, NGAL, NSE, TM and sTNFR1; CRP, IL2, IL8,MCP1, MMP9NGAL and TNFα; EGF, IL1α, IL8, MMP9NGAL, NSE, vWF and CK18;EGF, IL6, IL8, MMP9NGAL, NSE, VEGF and vWF; or CRP, IL1α, IL6, IL8,MMP9NGAL, NSE and VEGF are measured in a urine sample obtained from thesubject.

If the subject has a history of exposure to occupational risks orhazardous chemicals the levels of IL2, IL10, NGAL, NSE and VEGF; CEA,IL4, IL8, NGAL and TM; CEA, CRP, NGAL, NSE and sTNFR1; d-Dimer, CRP,IL6, IL8, NSE and sTNFR1; CEA, IL4, IL10, IFNγ, MCP1 and NGAL; FPSA,IL4, IL8, MMP9NGAL, NSE and sTNFR1; FPSA, IL1β, IL2, IL4, IL8, MMP9NGALand NGAL; CEA, d-Dimer, IL8, IL10, IFNγ, NGAL and NSE; and CEA, EGF,CRP, IL10, MCP1, NGAL and NSE VEGF are measured in a serum sampleobtained from the subject.

If the subject has a history of exposure to occupational risks orhazardous chemicals the levels of IL1α, IL6, MMP9NGAL, TM and sTNFR1;IL1α, IL1β, IL6, IL8 and TNFα; IL8, MMP9NGAL, NGAL, NSE and TNFα; IL1β,IL2, IL8, MMP9NGAL, NGAL and NSE; IL1β, IL8, IL10, MCP1, NGAL and TM;IL8, IFNγ, MMP9NGAL, TM, sTNFR1 and TNFα; IL1β, IL8, IFNγ, MCP1,MMP9NGAL, TM and sTNFR1; IL1α, IL4, IL8, IL10, MCP1, TM and sTNFR1; orIL1α, IL1β, IL6, IL8, NGAL, NSE and VEGF are measured in a plasma sampleobtained from the subject.

If the subject does not have a history of exposure to occupational risksor hazardous chemicals the levels of serum CEA, serum d-Dimer, urinaryEGF and serum IL1α; serum CEA, serum d-Dimer, serum IL6 and serum MCP1;or urinary BTA, serum CEA, urinary TNFα and urinary CK18 are measured.

If the subject does not have a history of exposure to occupational risksor hazardous chemicals the levels of BTA, TM, TNFα, sTNFR2 and vWF; BTA,TM, TNFα, vWF and FAS; EGF, NSE, TNFα, vWF and HA; IL6, MCP1, TNFα, vWF,FAS and CK18; BTA, d-Dimer, CRP, TNFα, vWF and HA; BTA, IL1α, TNFα, vWF,HA and FAS; BTA, d-Dimer, MMP9NGAL, TM, TNFα, vWF and HA; IL6, NGAL,sTNFR, TNFα, vWF, FAS and CK18; or BTA, IL1α, IL1β, IL6, NGAL, TNFα andCK18 are measured in a urine sample obtained from the subject.

If the subject does not have a history of exposure to occupational risksor hazardous chemicals the levels of CEA, d-Dimer, NSE, TM and TPSA;CEA, EGF, IL10, MCP1 and sTNFR1; CEA, d-Dimer, CRP, MCP1 and NGAL; CEA,d-Dimer, EGF, IL8, IL10 and TM; CEA, d-Dimer, IL4, MCP1, MMP9NGAL andsTNFR1; CEA, d-Dimer, EGF, IL6, NGAL and TM; CEA, d-Dimer, IL4, IL10,MCP1, MMP9NGAL and NSE; CEA, d-Dimer, IFNγ, MCP1, MMP9NGAL, TM and TPSA;or CEA, d-Dimer, EGF, IL6, IL10, MMP9NGAL and TM are measured in a serumsample obtained from the subject.

If the subject does not have a history of exposure to occupational risksor hazardous chemicals the levels of IL4, IL6, IFNγ, MMP9NGAL and NGAL;IL1β, IL4, IL10, MMP9NGAL and TM; IL2, IL4, IL6, IFNγ and MMP9NGAL; IL2,IL4, IL10, MMP9NGAL, TNFα and VEGF; CRP, IL4, IL10, MMP9NGAL, TNFα andVEGF; IL1α, IL4, IL10, IFNγ, MMP9NGAL and NSE; IL4, IL6, IL10, MMP9NGAL,NGAL, sTNFR1 and VEGF; d-Dimer, CRP, IL1α, IL1β, IL2, IL4 and MMP9NGAL;or d-Dimer, CRP, IL1β, IL4, IL6, IL10 and MMP9NGAL are measured in aplasma sample obtained from the subject.

If the subject has a history of anti-cholesterol medication the levelsof serum MCP1, plasma MCP1, serum NGAL and plasma NGAL; urinary CRP,serum IL2, serum NGAL and plasma NGAL; or urinary Creatinine, serumNGAL, plasma NGAL and plasma VEGF are measured.

If the subject has a history of anti-cholesterol medication the levelsof CRP, MCP1, sTNFR2, vWF and FAS; d-Dimer, IL6, MMP9NGAL, NSE and VEGF;BTA, MCP1, sTNFR2, vWF and FAS; d-Dimer, IL6, NGAL, NSE, VEGF and HA;IL1β, IL6, IL8, MMP9NGAL, NSE and VEGF; BTA, d-Dimer, IL6, NGAL, NSE andVEGF; BTA, CRP, IL1β, IL8, sTNFR2, vWF and FAS; d-Dimer, IL4, IL6, MMP9,NSE, VEGF and CK18; or BTA, CRP, IL1α, IL2, sTNFR2, vWF and FAS aremeasured in a urine sample obtained from the subject.

If the subject has a history of anti-cholesterol medication the levelsof IL6, IL8, NGAL, TPSA and VEGF; FPSA, NGAL, TM, TNFα and VEGF; IL1β,IL2, NGAL, TM and VEGF; IL1α, MCP1, MMP9NGAL, NGAL, TM and TNFα; CEA,FPSA, IL8, NGAL, TM and VEGF; FPSA, IL4, NGAL, NSE, TNFα and VEGF; FPSA,IL1β, IL10, NGAL, TM, TNFα and VEGF; CEA, IL1β, IL4, NGAL, TM, TPSA andVEGF; or FPSA, IL1β, IL4, IL10, NGAL, TM and VEGF are measured in aserum sample obtained from the subject.

If the subject has a history of anti-cholesterol medication the levelsof IL2, IFNγ, MCP1, MMP9NGAL and TM; IL1α, IL1β, IL6, TNFα and VEGF;IL4, IL6, IFNγ, MCP1 and TNFα; d-Dimer, IL2, IL6, MMP9NGAL, TM and TNFα;IL2, IL10, IFNγ, MCP1, MMP9NGAL and TNFα; IL6, MCP1, NGAL, NSE, TM andTNFα; d-Dimer, EGF, IL6, IL10, IFNγ, MCP1 and TNFα; d-Dimer, IL10, IFNγ,MCP1, NGAL, sTNFR and VEGF; or d-Dimer, IL6, IL8, IL10, NSE, TM and TNFαare measured in a plasma sample obtained from the subject.

If the subject does not have a history of anti-cholesterol medicationthe levels of serum CEA, urinary EGF, urinary HA and urinary CK18; serumCEA, urinary EGF, urinary IL8 and urinary CK18; or serum CEA, urinaryEGF, plasma IL6 and urinary MMP9NGAL are measured.

If the subject does not have a history of anti-cholesterol medicationthe levels of BTA, CRP, IL2, IL4 and CK18; EGF, IL1β, NGAL, VEGF andCK18; BTA, IL4, IL8, HA and CK18; EGF, CRP, IL4, VEGF, HA and CK18; EGF,IL4, IL6, IL8, vWF and CK18; BTA, EGF, IL4, IL8, HA and CK18; BTA, EGF,CRP, IL4, sTNFR1, HA and CK18; EGF, IL1α, IL1β, IL4, sTNFR1, VEGF andCK18; or EGF, CRP, IL4, MMP9NGAL, NGAL, HA and CK18 are measured in aurine sample obtained from the subject.

If the subject does not have a history of anti-cholesterol medicationthe levels of CEA, FPSA, IL10, IFNγ and NGAL; CEA, IL1α, IL1β, MMP9NGALand sTNFR1; CEA, IL1α, MMP9NGAL, TM and TNFα; CEA, IL1α, IL1β, IL6, NGALand NSE; CEA, IL4, IL6, IL8, MMP9NGAL and TNFα; CEA, d-Dimer, IL1α, IL4,IL6 and sTNFR1; CEA, IL1α, IL4, IL6, IL8, TM and sTNFR1; CEA, IL1α,IL1β, IL4, IL8, MMP9NGAL and VEGF; or CEA, IL1α, IL4, IL10, MMP9NGAL, TMand TNFα are measured in a serum sample obtained from the subject.

If the subject does not have a history of anti-cholesterol medicationthe levels of IL1α, IL8, MMP9NGAL, NGAL and sTNFR1; IL1α, IL1β, IL4,IFNγ and psTNFR1; IL1α, IL1β, IL8, TM and psTNFR1; d-Dimer, IL1α, IL4,IL10, MMP9NGAL and TNFα; CRP, IL8, IL10, MMP9NGAL, TM and sTNFR1;d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1; IL1β, IL6, IL8, MMP9NGAL,sTNFR1, TNFα and VEGF; d-Dimer, IL1α, IL4, IL8, NGAL, TM and sTNFR1; orIL1α, IL1β, IL4, IL6, IL8, MMP9NGAL and sTNFR1 are measured in a plasmasample obtained from the subject.

If the subject has proteinuria the levels of serum CEA, plasma CRP,urinary IL8 and plasma TNFα; urinary EGF, urinary IL1β, serum IL6 andurinary vWF; or serum CEA, plasma IL1α, urinary NSE and serum NSE aremeasured.

If the subject has proteinuria the levels of EGF, IL2, NSE, TM and CK18;EGF, IL6, sTNFR1, HA and CK18; EGF, NGAL, vWF, HA and CK18; EGF, IL8,sTNFR2, VEGF, uvWF and HA; EGF, IL1α, MMP9, NSE, uvWF and HA; EGF, CRP,IL2, IL4, TM and CK18; EGF, IL1β, IL2, NSE, TM, VEGF and vWF; EGF, IL1β,MMP9, MMP9NGAL, TNFα, vWF and HA; or EGF, IL2, IL4, NGAL, NSE, TM andCK18 are measured in a urine sample obtained from the subject.

If the subject has proteinuria the levels of CEA, IL8, IL10, NSE andTNFα; CEA, IL2, IL8, MMP9NGAL and NSE; CEA, IL2, IL6, IL10 and NSE; CEA,IL1β, IL2, IL8, IL10 and NSE; CEA, IL1β, IL2, IL8, NSE and TPSA; CEA,CRP, IL10, MMP9NGAL, NGAL and VEGF; CEA, IL1β, IL2, IL4, IL8, NSE andTNFα; CEA, EGF, IL4, IL8, IL10, TPSA and VEGF; or CEA, IL1β, IL2, IL4,IL10, MMP9NGAL and TM are measured in a serum sample obtained from thesubject.

If the subject has proteinuria the levels of CRP, IL1α, IL8, IFNγ, TM;CRP, IL1α, IL8, IFNγ, NGAL; IL1α, IL2, IL8, MCP1, TM; EGF, IL1α, IL4,IL8, IFNγ, TM; d-Dimer, IL1α, IL8, IFNγ, MCP1, TM; IL1α, IL8, IFNγ,MCP1, TM, TNFα; IL1α, IL2, IL8, IL10, IFNγ, MCP1, TM; IL1α, IL2, IL8,IFNγ, MCP1, MMP9NGAL, TM; or EGF, CRP, IL1α, IL4, IL8, IFNγ, TNFα aremeasured in a plasma sample obtained from the subject.

If the subject does not have proteinuria the levels of urinary BTA,urinary NGAL, serum NGAL and urinary TNFα; urinary d-Dimer, urinary CRP,urinary NGAL and serum TNFα; or serum CEA, urinary CRP, plasma MMP9NGALand urinary NGAL are measured.

If the subject does not have proteinuria the levels of d-Dimer, CRP,IL4, NGAL and sTNFR2; CRP, MMP9NGAL, NGAL, sTNFR2 and VEGF; BTA, CRP,IL4, NGAL and sTNFR2; CRP, MCP1, MMP9, NGAL, sTNFR2 and VEGF; d-Dimer,CRP, IL2, IL4, NGAL and sTNFR; BTA, CRP, IL2, NGAL, sTNFR2 and vWF;d-Dimer, CRP, IL1α, IL4, MMP9NGAL, TM and CK18; BTA, EGF, CRP, MMP9,NGAL, vWF and FAS; or BTA, CRP, NGAL, NSE, TM, sTNFR2 and vWF aremeasured in a urine sample obtained from the subject.

If the subject does not have proteinuria the levels of FPSA, IL1α, IL4,IFNγ and NGAL; d-Dimer, IL2, IL4, NGAL and TM; d-Dimer, IL6, NGAL, TMand sTNFR1; d-Dimer, IL1β, IL8, NGAL, TM and TNFα; CEA, IL4, IL8, NGAL,TNFα and TPSA; d-Dimer, FPSA, IL2, IL6, IL8 and NGAL; FPSA, CRP, IL2,IL6, NGAL, TNFα and VEGF; CEA, FPSA, CRP, IL6, IL10, NGAL and VEGF; ord-Dimer, FPSA, IL1β, IFNγ, MMP9NGAL, NGAL and TM are measured in a serumsample obtained from the subject.

If the subject does not have proteinuria the levels of d-Dimer, IL4,MCP1, MMP9NGAL and TNFα; EGF, IL1α, IL2, MMP9NGAL and NGAL; d-Dimer,IL4, MCP1, MMP9NGAL and sTNFR1; d-Dimer, IL1β, IL4, IL8, IL10 andMMP9NGAL; d-Dimer, EGF, IL8, IL10, MMP9NGAL and TM; d-Dimer, EGF, IFNγ,MMP9NGAL, NSE and VEGF; EGF, IL1α, IL2, IL4, MCP1, MMP9NGAL and NGAL;d-Dimer, EGF, CRP, IL8, MMP9NGAL, NSE and VEGF; and d-Dimer, EGF, IL1β,IL8, IL10, MMP9NGAL and VEGF are measured in a plasma sample obtainedfrom the subject.

The “level” of a combination of biomarkers refers to the amount, thelevel or concentration of each biomarker of the combination ofbiomarkers within the sample.

The accuracy of the methods which are the subject of the invention isoften described by their receiver-operating characteristics (ROC).

The ROC graph is a plot of all of the sensitivity/specificity pairsresulting from continuously varying the decision threshold over theentire range of data observed. To construct a ROC curve for multiplebiomarkers, a logistic regression equation is derived for the biomarkercombination of interest, by inputting measured protein concentrationvalue of each of the biomarkers in a patient's sample into the equation.

Although a logistic regression equation is the preferred statisticalmethod for the current invention, other conventional statistical methodscan be used.

The combinations of biomarkers used to diagnose urothelial cancer in thepresent invention have a sensitivity and specificity of at least 70%.This means that out of 100 patients which have urothelial cancer, 70% ofthem will be correctly identified from the determination of the presenceof a particular combination of biomarkers as positive for urothelialcancer while out of 100 patients who do not have urothelial cancer 70%will accurately test negative for the disease.

A ROC plot depicts the overlap between the two distributions by plottingthe sensitivity versus 1—specificity for the complete range of decisionthresholds. On the y-axis is sensitivity, or the true-positive fractiondefined as [(number of true-positive test results)/(number oftrue-positive+number of false-negative test results)]. This has alsobeen referred to as positivity in the presence of a disease orcondition. It is calculated solely from the affected subgroup. On thex-axis is the false-positive fraction, or 1—specificity [defined as(number of false-positive results)/(number of true-negative+number offalse-positive results)]. It is an index of specificity and iscalculated entirely from the unaffected subgroup. Because the true- andfalse-positive fractions are calculated entirely separately, by usingthe test results from two different subgroups, the ROC plot isindependent of the prevalence of disease in the sample. Each point onthe ROC plot represents a sensitivity/specificity pair corresponding toa particular decision threshold. A test with perfect discrimination (nooverlap in the two distributions of results) has an ROC plot that passesthrough the upper left corner, where the true-positive fraction is 1.0,or 100% (perfect sensitivity), and the false-positive fraction is 0(perfect specificity). The theoretical plot for a test with nodiscrimination (identical distributions of results for the two groups)is a 45° diagonal line from the lower left corner to the upper rightcorner. Most plots fall in between these two extremes. Qualitatively,the closer the plot is to the upper left corner, the higher the overallaccuracy of the test.

One convenient goal to quantify the diagnostic accuracy of a laboratorytest is to express its performance by a single number. The most commonglobal measure is the area under the curve (AUC) of the ROC plot. Thearea under the ROC curve is a measure of the probability that theperceived measurement will allow correct identification of a condition.By convention, this area is always 0.5. Values range between 1.0(perfect separation of the test values of the two groups) and 0.5 (noapparent distributional difference between the two groups of testvalues). The area does not depend only on a particular portion of theplot such as the point closest to the diagonal or the sensitivity at 90%specificity, but on the entire plot. This is a quantitative, descriptivethe level of how close the ROC plot is to the perfect one (area=1.0).

Scores between 0 and 1 make it possible to assign a subject as a“low-risk control” (i.e. requiring primary care monitoring), a“high-risk control” (i.e. requiring close evaluation and furtherinvestigation), a “low-risk bladder cancer” (i.e. requiring urgentcystoscopy) or a “high-risk bladder cancer” (i.e. requiring immediatecystoscopy). Scores<0.4 indicate that the risk of serious disease islow, or if the initial diagnostic step has also been carried out andproduces a score<0.4, it is unlikely that the subject has UC. Ascore>0.6 indicates a high risk of serious disease, or that the patientcould have UC if the score is based on the initial diagnostic step.Scores between 0.4 and 0.6 can be interpreted as indicative of potentialrisk and the possibility of UC. Subjects with scores of 0.2 from themethod of the invention (and the initial diagnostic step if that iscarried out) and no clinical risk factors are identified as low-riskcontrols. Such subjects could be monitored in primary care.

The individual biomarkers identified by the present inventors as havingan altered level in subjects suffering form or having increased risk ofurothelial cancer compared to a control value are Bladder Tumour Antigen(BTA), Carcino-embryonic antigen (CEA), Human cytokeratin 18 (CK18),C-reactive protein (CRP), Creatinine, d Dimer, Epidermal growth factor(EGF), FAS, Hyaluronidase (HA), IL1α, IL1β, IL2, IL4, IL6, IL8, IL10,Interferon gamma (IFNγ), Monocyte Chemoattractant Protein 1 (MCP1),matrix metalloproteinase 9 (MMP9), Neutrophil gelatinase-associatedlipocalin (NGAL), MMP9NGAL complex, Neuron specific enolase (NSE), FreeProstate Specific Antigen (FPSA), Total Prostate Specific Antigen(TPSA), Thrombomodulin (TM), Tumour necrosis factor α (TNFα), sTNFR1,sTNFR2, Vascular endothelial growth factor (VEGF) and von Willebrandfactor (vWF). These biomarkers were identified by statistical analysisbased on a diagnostic algorithm of demographic variables which includeone or more of the patient's smoking history, age, history ofanti-hypertension medication, history of anti-cholesterol medication,history of alcohol consumption, history of exposure to occupationalrisks or hazardous chemicals, proteinuria and cytological detection ofinflammatory cells. Each of these demographic variables may be assigneda notional value which can be used in Forward Wald binary logisticregression analyses to create a diagnostic algorithm designated as PPP.PPP represents, in a single measure, the intrinsic contribution towardgroup membership with which each subject commences screening. Thecontribution that each biomarker makes to the area under the curve (AUC)values for the PPP algorithm can be assessed to determine whether acombination of biomarkers increases the statistical significance of thePPP algorithm.

A second aspect of the present invention provides a solid state devicefor diagnosis of urothelial cancer, the device comprising a substratecomprising an antibody that specifically binds one or more biomarkersselected from Bladder Tumour Antigen (BTA), Carcino-embryonic antigen(CEA), Human cytokeratin 18 (CK18), C-reactive protein (CRP),Creatinine, d Dimer, Epidermal growth factor (EGF), FAS, Hyaluronidase(HA), IL1α, IL1β, IL2, IL4, IL6, IL8, IL10, Interferon gamma (IFNγ),Monocyte Chemoattractant Protein 1 (MCP1), matrix metalloproteinase 9(MMP9), Neutrophil gelatinase-associated lipocalin (NGAL), MMP9NGALcomplex, Neuron specific enolase (NSE), Free Prostate Specific Antigen(FPSA), Total Prostate Specific Antigen (TPSA), Thrombomodulin (TM),Tumour necrosis factor α (TNFα), tumour necrosis factor Receptor 1(sTNFR1), tumour necrosis factor Receptor 2 (sTNFR2), Vascularendothelial growth factor (VEGF) and von Willebrand factor (vWF).

The antibodies used in the present invention can be of any conventionaltype. Polyclonal and monoclonal antibodies are preferred, withmonoclonal antibodies being most preferred.

A device that may be used in the invention may be prepared by activatingthe surface of a suitable substrate, and applying an array of antibodieson to discrete sites on the surface. If desired, the other active areasmay be blocked. The ligands may be bound to the substrate via a linker.In particular, it is preferred that the activated surface is reactedsuccessively with an organosilane, a bifunctional linker and theantibody. The solid state device used in the methods of the presentinvention may be manufactured according to the method disclosed in, forexample, GB-A-2324866 the content of which is incorporated herein in itsentirety. Preferably, the solid state device used in the methods of thepresent invention is the Biochip Array Technology system (BAT)(available from Randox Laboratories Limited). More preferably, theEvidence Evolution and Evidence Investigator apparatus (available fromRandox Laboratories) may be used to determine the levels of biomarkersin the sample.

The solid state device is used in combination with other clinicalindicators including the risk factors that might confound diagnosis ofurothelial cancer using biomarkers, to assess the risk of a subjecthaving urothelial cancer and/or stratify the level of risk of seriousdisease, wherein combination of antibodies present on the solid statedevice are selected according to a sub-population group that isappropriate to the subject.

At least one, but optionally two or more different solid state devicesaccording to the invention may be used for each individual subject inorder to assess their risk of having urothelial cancer. If multipledevices are used, each will comprise a combination of antibodiesselected according to sub-population groups that are appropriate to thesubject.

The solid state devices comprise antibodies that specifically bind tobiomarkers that allow diagnosis of urothelial cancer in subpopulationsof subjects according the invention. Such solid state devices fordiagnosis of urothelial cancer in subjects that have a history ofsmoking comprise antibodies that bind specifically to urinary EGF,urinary IL6, urinary VEGF and urinary CK18; urinary EGF, serum IL8,urinary vWF and urinary FAS; urinary EGF, urinary IL1α, plasma MMP9NGALand urinary vWF; EGF, IL1β, sTNFR, VEGF and CK18; BTA, EGF, IL1β, vWFand FAS; EGF, IL1β, IL8, TM, and vWF; d-Dimer, EGF, IL1β, IL8, VEGF andvWF; EGF, IL1β, NSE, sTNFR2, VEGF and vWF; EGF, IL2, TM, sTNFR2, VEGFand CK18; EGF, IL1α, MMP9, MMP9NGAL, NSE, VEGF and vWF; EGF, IL1β, NGAL,NSE, sTNFR1, VEGF and vWF; d-Dimer, EGF, IL1α, IL8, NSE, vWF and FAS;d-Dimer, EGF, IL1α, IL8 and NGAL; IL1α, IL2, IL8, NGAL and sTNFR1; IL1α,IL10, NGAL, NSE and TNFα; d-Dimer, IL2, IL10, MMP9NGAL, NGAL and sTNFR1;EGF, FPSA, IL10, NGAL, TNFα and TPSA; CEA, IL1α, IL4, IL8, IL10 andNGAL; EGF, CRP, IL10, MMP9NGAL, NGAL, TM and VEGF; CEA, CRP, IL10,MMP9NGAL, NGAL, TM and TNFα; CEA, d-Dimer, IL2, IL8, IL10, IFNγ and NSE;IL4, IFNγ, MCP1, MMP9NGAL and TM; IL1α, IL4, IFNγ, MCP1 and MMP9NGAL;EGF, IL1α, IL4, MCP1, MMP9NGAL; dDimer, IL1α, IL4, IL10, MMP9NGAL andsTNFR1; IL4, IL10, MMP9NGAL, TM, sTNFR1 and TNFα; IL1β, IL4, IL8, MCP1,MMP9NGAL and TNFα; IL1α, IL1β, IL2, IL4, IL10, MMP9NGAL and TNFαd-Dimer, IL1α, IL4, IFNγ, MCP1, MMP9NGAL and TM; or d-Dimer, EGF, IL1α,IL4, IL10, IFNγ, and MMP9NGAL.

The solid state devices for diagnosis of urothelial cancer in subjectsthat do not have a history of smoking comprise comprises antibodies thatbind specifically to serum CEA, urinary EGF, plasma IL8 and urinaryCK18; serum CEA, plasma IL8, serum NGAL and serum TM; serum CEA, plasmaIL8, serum NGAL and plasma NSE; BTA, MMP9NGAL, TM, sTNFR2 and VEGF; BTA,IL4, MMP9, NSE and FAS; BTA, MMP9NGAL, TNFα, sTNFR2 and VEGF; BTA, MCP1,MMP9, sTNFR2, vWF and FAS; d-Dimer, IL6, IL8, NGAL, NSE and TNFα; BTA,IL6, MCP1, TNFα, sTNFR2 and FAS; EGF, CRP, IL8, NGAL, NSE, TM and HA;BTA, EGF, IL8, MCP1, NGAL, NSE, sTNFR1; BTA, IL4, MCP1, TM, sTNFR2, vWFand FAS; CEA, EGF, IL4, NGAL and TNFα; CEA, EGF, IL8, NGAL and TPSA;CEA, IL8, MCP1, NGAL and TPSA; CEA, IL6, IL8, MMP9NGAL, NGAL and VEGF;CEA, d-Dimer, CRP, MMP9NGAL, NGAL and NSE; CEA, CRP, IL2, MMP9NGAL, NGALand TM; CEA, EGF, CRP, IL4, IL8, NGAL and NSE; CEA, IL6, IL8, IFNγ,NGAL, TM and VEGF; CEA, FPSA, CRP, IL4, MMP9NGAL, NGAL and TM; IL1α,MMP9NGAL, NSE, sTNFR1 and VEGF; IFNγ, MCP1, MMP9NGAL, NGAL and NSE;IFNγ, MMP9NGAL, NGAL, NSE and TNFα; IL6, IFNγ, MMP9NGAL, NGAL, NSE andTNFα; d-Dimer, IL1α, IL4, MMP9NGAL, NSE and VEGF; d-Dimer, EGF, IL1α,IL8, MMP9NGAL and NSE; d-Dimer, EGF, IL1α, IFNγ, MMP9NGAL, TNFα andVEGF; EGF, IL1α, IL2, MMP9NGAL, NGAL, NSE and TM; or IL1α, IFNγ,MMP9NGAL, NGAL, NSE, TM and TNFα.

The solid state devices for diagnosis of urothelial cancer in subjectsthat are aged 65 years or older comprise comprises antibodies that bindspecifically to serum IL2, serum MMP9NGAL, serum NGAL and plasma sTNFR1;urinary MMP9NGAL, serum NGAL, plasma NGAL and urinary vWF; serum CEA,serum d-Dimer, plasma d-Dimer and serum IFNγ; BTA, IL1β, VEGF, vWF andHA; d-Dimer, IL1α, NSE, vWF and HA; BTA, d-Dimer, IL1β, vWF and HA; BTA,IL1β, IL4, VEGF, vWF and HA; BTA, IL1β, IL8, sTNFR2, vWF and HA; BTA,EGF, IL1α, NSE, vWF and HA; d-Dimer, CRP, IL1α, IL2, NSE, vWF and HA;BTA, IL1α, IL8, MMP9NGAL, vWF, HA and CK18; d-Dimer, IL1α, MCP1, NSE,TNFα, vWF and HA; CEA, d-Dimer, IL4, NGAL and TM; IL1α, MMP9NGAL, NGAL,sTNFR1 and TNFα; IL2, MMP9NGAL, NGAL, sTNFR1 and VEGF; CEA, d-Dimer,IL1α, NGAL, NSE and TM; CEA, EGF, IL1α, MMP9NGAL, NGAL and TPSA; CEA,d-Dimer, CRP, IL1β, NGAL and TM; CEA, d-Dimer, FPSA, CRP, IL10, NGAL andTM; CEA, d-Dimer, CRP, NGAL, NSE, TM and TPSA; d-Dimer, IL1α, IL8, IFNγ,MMP9NGAL, NGAL and TM; CRP, IL1α, MMP9NGAL, TM and VEGF; CRP, IL1α,IL1β, MMP9NGAL and NGAL; CRP, IL1α, IL4, MMP9NGAL and TM; CRP, IL1α,IL2, IL4, MMP9NGAL and TM; EGF, CRP, IL1α, IL1β, MMP9NGAL and VEGF; EGF,IL1α, IL6, MMP9NGAL, TM and TNFα; CRP, IL1α, IL10, MMP9NGAL, TM, TNFαand VEGF; IL1α, IL6, IL10, MMP9NGAL, TM, TNFα and VEGF; or CRP, IL1α,IL4, IL6, MMP9NGAL, TM and TNFα.

The solid state devices for diagnosis of urothelial cancer in subjectsthat are less than 65 years old comprise antibodies that bindspecifically to serum CEA, urinary EGF, serum IL1α and urinary VEGF;serum CEA, urinary CRP, serum IL1α and urinary VEGF; serum CEA,serum-IL1α, plasma IFNγ and urinary VEGF; EGF, IL2, HA, FAS and CK18;EGF, IL2, MMP9NGAL, HA and CK18; EGF, vWF, HA, FAS and CK18; EGF, IL2,IL8, MMP9, HA and CK18; BTA, EGF, IL1β, IL8, HA and CK18; d-Dimer, EGF,NSE, vWF, HA and CK18; EGF, CRP, IL1β, IL2, IL8, HA and CK18; EGF, IL1β,IL4, IL8, vWF, HA and CK18; EGF, IL1β, IL6, IL8, MMP9, HA and CK18; CEA,IL1α, IL4, TM and TNFα; CEA, IL1α, IL2, IL4 and IL8; CEA, IL1α, IL1β,IL4 and VEGF; CEA, IL1α, IL4, IL8, MMP9NGAL and sTNFR1; CEA, IL1α, IL2,IL4, NSE and sTNFR1; CEA, EGF, IL1α, IL4, IL8 and TM; CEA, IL1α, IL2,IL4, IL8, IFNγ and MMP9NGAL; CEA, EGF, FPSA, IL1α, IL4, IL8 and VEGF;CEA, IL1α, IL2, IL8, IFNγ, MCP1 and sTNFR1; d-Dimer, IL8, IL10, NSE andVEGF; d-Dimer, IL8, MMP9NGAL, TNFα and VEGF; EGF, IL8, IL10, MMP9NGALand sTNFR1; EGF, CRP, IL6, IL8, IL10 and sTNFR1; CRP, IL6, IL8, IL10,IFNγ and sTNFR1; d-Dimer, IL4, IL8, MMP9NGAL, NGAL and TNFα; CRP, IL4,IL6, IL8, IL10, MMP9NGAL and TNFα; EGF, CRP, IL1β, IL8, IFNγ, NGAL andsTNFR1; or d-Dimer, EGF, CRP, IL8, IL10, IFNγ and MMP9NGAL.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has a history of anti-hypertensive medication comprises antibodiesthat bind specifically to urinary EGF, urinary SERUM-IL1α, IL1α, serumIL10 and urinary vWF; urinary EGF, plasma IL10, urinary VEGF and urinaryvWF; serum sTNFR1, plasma sTNFR1, serum TNFα and urinary vWF; CRP, IL2,IL8, sTNFR2 and vWF; EGF, IL8, NSE, TNFα and vWF; BTA, EGF, IL4, vWF andHA; BTA, EGF, IL1β, IL8, VEGF and vWF; d-Dimer, CRP, IL8, sTNFR2, vWFand CK18; d-Dimer, EGF, IL2, VEGF, vWF and FAS; CRP, IL1β, IL6, IL8,MMP9, NGAL and vWF; d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 and vWF; BTA,d-Dimer, EGF, IL4, NGAL, NSE and vWF; CEA, NGAL, NSE, TNFα and TPSA;CEA, MMP9NGAL, NGAL, TM and TNFα; CEA, IL1β, NGAL, sTNFR1 and TPSA; CEA,IL1β, IL10, NGAL, TM and VEGF; CEA, d-Dimer, IL1β, MMP9NGAL, NGAL andTM; CEA, EGF, IL1α, IL1β, NGAL and TNFα; CEA, IL1α, IL1β, IL10, NGAL,sTNFR1 and TNFα; CEA, IL1α, NGAL, NSE, TM, TNFα and TPSA; CEA, IL1β,IL4, IL10, MMP9NGAL, NGAL and TM; IL1α, IL1β, IL4, IFNγ and VEGF; EGF,CRP, IL2, IL4 and IL8; EGF, CRP, IL2, IL10 and NGAL; EGF, IL6, IL10,IFNγ, MCP1 and MMP9NGAL; d-Dimer, EGF, IL1β, IL4, IL6 and MCP1; EGF,CRP, IL1β, IL2, MMP9NGAL and NGAL; d-Dimer, EGF, CRP, IL2, IL10,MMP9NGAL and TM; CRP, IL1α, IL1β, IL4, IL6, IFNγ and sTNFR1; or EGF,CRP, IL4, IL6, IL10, IFNγ and MMP9NGAL.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have a history of anti-hypertensive medication comprisesantibodies that bind specifically to serum CEA, urinary CRP, urinary NSEand serum TNFα; serum CEA, urinary CRP, serum IL4 and urinary sTNFR1;urinary Creatinine, serum IL6, plasma MMP9NGAL and urinary VEGF; CRP,NGAL, VEGF, HA and CK18; d-Dimer, TNFα, VEGF, HA and CK18; MMP9, NSE,TM, VEGF and FAS; EGF, NGAL, VEGF, vWF, HA and CK18; CRP, IL1β, IL6,sTNFR1, VEGF and vWF; d-Dimer, EGF, IL4, VEGF, HA and CK18; CRP, IL1β,IL6, IL8, MMP9, NGAL and vWF; d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 andvWF; BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF; CEA, d-Dimer, IL4,MMP9NGAL and sTNFR1; CEA, EGF, IL10, MMP9NGAL and TNFα; CEA, d-Dimer,CRP, IL4 and IL10; CEA, d-Dimer, CRP, IL4, IL10 and TM; CEA, d-Dimer,CRP, IL4, IL6 and MMP9NGAL; CEA, d-Dimer, IL2, IL4, IL8 and MMP9NGAL;CEA, d-Dimer, EGF, IL4, IL8, IL10 and NSE; CEA, d-Dimer, CRP, IL4, MCP1,MMP9NGAL and TNFα; CEA, d-Dimer, CRP, IL4, IL6, TM and TNFα; EGF, IL1α,IL8, MMP9NGAL and VEGF; IL1α, IL8, IFNγ, MMP9NGAL and VEGF; CRP, IL1α,IL8, MMP9NGAL and NGAL; EGF, CRP, IL1β, IL8, MMP9NGAL and VEGF; CRP,IL1α, IL6, IL8, IL10, MMP9NGAL; EGF, IL1β, IL4, IL8, MMP9NGAL and VEGF;EGF, CRP, IL1α, IL8, MMP9NGAL, TNFα and VEGF; EGF, CRP, IL1β, IL8,MMP9NGAL, sTNFR1 and VEGF; or d-Dimer, EGF, IL1β, IL6, IL8, MMP9NGAL andVEGF.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has cytological detection of inflammatory cells comprisesantibodies that bind specifically to urinary BTA, serum CEA, plasma IL10and urinary CK18; urinary BTA, plasma IL6, serum NSE and plasma NSE;urinary dipstick protein, urinary BTA, plasma IL6 and serum NGAL; BTA,IL1α, NGAL, sTNFR1 and vWF; BTA, IL8, MMP9NGAL, VEGF and CK18; BTA, IL6,MMP9NGAL, NSE and CK18; BTA, IL2, MMP9NGAL, sTNFR1, TNFα and VEGF; BTA,IL2, MMP9NGAL, NGAL, TNFα and CK18; BTA, IL2, MMP9NGAL, NSE, VEGF andCK18; BTA, IL2, MMP9NGAL, NGAL, sTNFR1, TNFα and VEGF; BTA, IL2,MMP9NGAL, TM, sTNFR1, vWF and FAS; BTA, IL2, MMP9NGAL, sTNFR1, VEGF, vWFand CK18; CEA, IL1α, NGAL, NSE and TPSA; IL1α, MMP9NGAL, NGAL, TPSA andVEGF; CEA, IL1α, IL10, NGAL and VEGF; CEA, IL10, MMP9NGAL, NGAL, TNFαand VEGF; IL1α, IL10, MMP9NGAL, NGAL, NSE and VEGF; CRP, IL10, MMP9NGAL,NGAL, TPSA and VEGF; CEA, CRP, IL1β, IL2, TM, sTNFR1 and TPSA; CRP,IL1β, IL2, IL6, MMP9NGAL, NGAL and TNFα; CRP, IL1β, IL2, MMP9NGAL, NGAL,NSE and TNFα; IL1α, IL6, IL8, MMP9NGAL and NSE; IL6, IFNγ, MMP9NGAL, NSEand sTNFR1; IL1α, IL1β, IL8, IL10 and MMP9NGAL; IL6, IL8, IFNγ,MMP9NGAL, NGAL and NSE; IL1α, IL6, MMP9NGAL, NSE, TM and TNFα; d-Dimer,IL4, IL8, IFNγ, MMP9NGAL and VEGF; IL1α, IL8, IL10, MCP1, MMP9NGAL, NSEand TM; d-Dimer, IL2, IL6, IL8, MMP9NGAL, TM and sTNFR1; or IL1α, IL2,IL6, IL8, MCP1, MMP9NGAL and NSE.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have cytological detection of inflammatory cells comprisesantibodies that bind specifically to serum CEA, plasma IL8, serum TNFαand urinary FAS; urinary EGF, serum EGF, serum FPSA and serum IL4;urinary EGF, urinary CRP, urinary IL4 and urinary NSE; EGF, CRP, IL4, TMand vWF; BTA, d-Dimer, EGF, CRP and IL4; EGF, CRP, IL4, IL6 and vWF;d-Dimer, EGF, CRP, IL4, sTNFR1 and vWF; d-Dimer, EGF, CRP, IL4, sTNFR1and sTNFR2; EGF, IL2, IL4, sTNFR2, VEGF and vWF; EGF, CRP, IL4, MCP1,VEGF, FAS and CK18; d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and vWF;d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and CK18; CEA, EGF, CRP, IL4 andIFNγ; d-Dimer, FPSA, IL6, IFNγ and NGAL; IL1α, IL4, MMP9NGAL, NGAL andTM; IL4, MMP9NGAL, NGAL, NSE, sTNFR1 and TPSA; CEA, EGF, FPSA, IL4, NSEand sTNFR1; CEA, EGF, FPSA, IL4, MCP1 and VEGF; FPSA, IL2, IL4, IL6,MMP9NGAL, NGAL and sTNFR1; CEA, EGF, FPSA, CRP, IL4, IL6 and MMP9NGAL;d-Dimer, IL1β, IL4, IL8, MCP1, NGAL and TM; d-Dimer, IL1β, IL8, MMP9NGALand TM; d-Dimer, IL8, TM, TNFα and VEGF; IL2, IL8, MMP9NGAL, TM andTNFα; d-Dimer, IL8, MMP9NGAL, NSE, TM and TNFα; d-Dimer, IL2, IL8,MMP9NGAL, NSE and TNFα; d-Dimer, IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα;d-Dimer, IL1α, IL8, MMP9NGAL, TM, TNFα and VEGF; d-Dimer, CRP, IL2, IL6,IL8, MMP9NGAL and TNFα; or d-Dimer, IL1α, IL1β, IL8, MMP9NGAL, TM andVEGF.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has a history of alcohol consumption comprises antibodies that bindspecifically to urinary EGF, urinary IL1β, plasma MMP9NGAL and urinaryvWF; serum CEA, urinary EGF, urinary vWF and urinary CK18; serum CEA,urinary EGF, plasma NSE and urinary vWF; EGF, MMP9, sTNFR2, VEGF andvWF; EGF, IL1α, IL4, vWF and FAS; EGF, IL1α, MMP9, vWF and HA; d-Dimer,EGF, CRP, IL1α, IL6 and vWF; EGF, CRP, IL1α, sTNFR, vWF and CK18; BTA,EGF, CRP, IL1α, vWF and FAS; EGF, IL1α, IL6, NGAL, sTNFR2, vWF and FAS;EGF, IL1α, IL2, IL6, NGAL, VEGF and vWF; EGF, IL1α, NGAL, NSE, sTNFR2,vWF and CK18; CRP, IL1β, IL6, IL8 and NGAL; d-Dimer, IL1β, IL4, IFNγ andNGAL; CRP, IL1β, IL4, MCP1 and NGAL; EGF, CRP, IL1α, IL1β, NGAL andTPSA; CEA, CRP, IL1β, IL2, NGAL and NSE; CEA, d-Dimer, CRP, IL1α, IL6and NGAL; EGF, CRP, IL8, MCP1, MMP9NGAL, NGAL and sTNFR1; CEA, EGF, CRP,IL1β, MMP9NGAL, NGAL and TM; CEA, d-Dimer, IL1α, IL2, IL4, IL10 andNGAL; d-Dimer, IL4, MMP9NGAL, NSE and TM; IL1β, IL4, MMP9NGAL, NSE andTNFα; EGF, CRP, IL4, MMP9NGAL and sTNFR1; IL1α, IL2, IL4, MMP9NGAL, NSEand TNFα; IL2, IL4, IL6, MMP9NGAL, NSE and TM; CRP, IL1α, IL1β, IL4,MMP9NGAL and TNFα; d-Dimer, IL1β, IL4, MMP9NGAL, NGAL, NSE and VEGF;d-Dimer, IL1α, IL2, MMP9NGAL, NSE, sTNFR and TNFα; or d-Dimer, CRP,IL1α, IL4, IL10, NSE and sTNFR.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have a history of alcohol consumption comprises antibodiesthat bind specifically to serum MMP9NGAL, serum sTNFR1, serum TNFα andurinary VEGF; serum CEA, urinary EGF, serum IL10 and serum NGAL; urinaryIL6, plasma MMP9NGAL, urinary VEGF and urinary CK18; IL2, IL8, NGAL, HAand CK18; IL2, IL4, VEGF, HA and CK18; IL1β, IL2, IL8, NGAL and CK18;IL2, IL4, IL8, NGAL, HA and CK18; BTA, d-Dimer, IL2, IL8, MMP9NGAL andCK18; IL2, IL4, IL8, sTNFR2, HA and CK18; IL1β, IL2, IL6, IL8, NGAL, NSEand CK18; IL1α, IL2, IL6, IL8, NGAL, HA and CK18; BTA, IL1α, IL2, IL8,NGAL, VEGF and CK18; CEA, IL1α, IL8, TM and sTNFR1; CEA, IL1α, IL6, NGALand TM; CEA, IL1α, IL2, TM and sTNFR1; CEA, IL2, IL8, NSE, TM andsTNFR1; CEA, IL10, MMP9NGAL, NSE, TM and sTNFR1; CEA, CRP, IL2, IL10,NGAL and TM; CEA, CRP, IL4, IL6, IL10, sTNFR1 and TPSA; CEA, d-Dimer,EGF, IL1α, IL10, NSE and sTNFR1; CEA, d-Dimer, IL1α, IL1β, IL4, TM andsTNFR1; IL1α, IFNγ, MMP9NGAL, sTNFR1 and TNFα; EGF, IL4, MCP1, MMP9NGALand sTNFR1; IL1α, IL8, IL10, MMP9NGAL and VEGF; IL1α, IL1β, IL10, IFNγ,MMP9NGAL and VEGF; EGF, CRP, IL1α, MMP9NGAL, TNFα and VEGF; IL1α, IL6,IL8, IFNγ, MMP9NGAL and sTNFR1; L1α, IL2, IL8, IFNγ, MMP9NGAL, sTNFR1and TNFα; IL1α, IL2, IL6, IL10, MMP9NGAL, TNFα and VEGF; or IL1α, IL4,IL6, IL10, MMP9NGAL, NGAL and VEGF.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has a history of exposure to occupational risk or hazardouschemicals comprises antibodies that bind specifically to serum CEA,urinary EGF, urinary VEGF and urinary vWF; urinary EGF, serum IL8,urinary vWF and urinary HA; serum IL4, plasma IL8, serum MCP1 andurinary VEGF; BTA, IL2, IL4, MMP9NGAL and VEGF; BTA, IL1α, IL8, NGAL andNSE; BTA, CRP, IL4, NSE and CK18; BTA, d-Dimer, CRP, IL4, sTNFR1 andvWF; IL4, IL8, NGAL, NSE, TM and sTNFR1; CRP, IL2, IL8, MCP1, MMP9NGALand TNFα; EGF, IL1α, IL8, MMP9NGAL, NSE, vWF and CK18; EGF, IL6, IL8,MMP9NGAL, NSE, VEGF and vWF; CRP, IL1α, IL6, IL8, MMP9NGAL, NSE andVEGF; IL2, IL10, NGAL, NSE and VEGF; CEA, IL4, IL8, NGAL and TM; CEA,CRP, NGAL, NSE and sTNFR1; d-Dimer, CRP, IL6, IL8, NSE and sTNFR1; CEA,IL4, IL10, IFNγ, MCP1 and NGAL; FPSA, IL4, IL8, MMP9NGAL, NSE andsTNFR1; FPSA, IL1β, IL2, IL4, IL8, MMP9NGAL and NGAL; CEA, d-Dimer, IL8,IL10, IFNγ, NGAL and NSE; CEA, EGF, CRP, IL10, MCP1, NGAL and NSE; IL1α,IL6, MMP9NGAL, TM and sTNFR1; IL1α, IL1β, IL6, IL8 and TNFα; IL8,MMP9NGAL, NGAL, NSE and TNFα; IL1β, IL2, IL8, MMP9NGAL, NGAL and NSE;IL1β, IL8, IL10, MCP1, NGAL and TM; IL8, IFNγ, MMP9NGAL, TM, sTNFR1 andTNFα; IL1β, IL8, IFNγ, MCP1, MMP9NGAL, TM and sTNFR1; IL1α, IL4, IL8,IL10, MCP1, TM and sTNFR1; or IL1α, IL1β, IL6, IL8, NGAL, NSE and VEGF.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have a history of exposure to occupational risk orhazardous chemicals comprises antibodies that bind specifically to serumCEA, serum d-Dimer, urinary EGF and serum IL1α; serum CEA, serumd-Dimer, serum IL6 and serum MCP1; urinary BTA, serum CEA, urinary TNFαand urinary CK18; BTA, TM, TNFα, sTNFR2 and vWF; BTA, TM, TNFα, vWF andFAS; EGF, NSE, TNFα, vWF and HA; IL6, MCP1, TNFα, vWF, FAS and CK18;BTA, d-Dimer, CRP, TNFα, vWF and HA; BTA, IL1α, TNFα, vWF, HA and FAS;BTA, d-Dimer, MMP9NGAL, TM, TNFα, vWF and HA; IL6, NGAL, sTNFR, TNFα,vWF, FAS and CK18; BTA, IL1α, IL1β, IL6, NGAL, TNFα and CK18; CEA,d-Dimer, NSE, TM and TPSA; CEA, EGF, IL10, MCP1 and sTNFR1; CEA,d-Dimer, CRP, MCP1 and NGAL; CEA, d-Dimer, EGF, IL8, IL10 and TM; CEA,d-Dimer, IL4, MCP1, MMP9NGAL and sTNFR1; CEA, d-Dimer, EGF, IL6, NGALand TM; CEA, d-Dimer, IL4, IL10, MCP1, MMP9NGAL and NSE; CEA, d-Dimer,IFNγ, MCP1, MMP9NGAL, TM and TPSA; CEA, d-Dimer, EGF, IL6, IL10,MMP9NGAL and TM; IL4, IL6, IFNγ, MMP9NGAL and NGAL; IL1β, IL4, IL10,MMP9NGAL and TM; IL2, IL4, IL6, IFNγ and MMP9NGAL; IL2, IL4, IL10,MMP9NGAL, TNFα and VEGF; CRP, IL4, IL10, MMP9NGAL, TNFα and VEGF; IL1α,IL4, IL10, IFNγ, MMP9NGAL and NSE; IL4, IL6, IL10, MMP9NGAL, NGAL,sTNFR1 and VEGF; d-Dimer, CRP, IL1α, IL1β, IL2, IL4 and MMP9NGAL; ord-Dimer, CRP, IL1β, IL4, IL6, IL10 and MMP9NGAL.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has a history of anti-cholesterol medication comprises antibodiesthat bind specifically to serum MCP1, plasma MCP1, serum NGAL and plasmaNGAL; urinary CRP, serum IL2, serum NGAL and plasma NGAL; urinaryCreatinine, serum NGAL, plasma NGAL and plasma VEGF; CRP, MCP1, sTNFR2,vWF and FAS; d-Dimer, IL6, MMP9NGAL, NSE and VEGF; BTA, MCP1, sTNFR2,vWF and FAS; d-Dimer, IL6, NGAL, NSE, VEGF and HA; IL1β, IL6, IL8,MMP9NGAL, NSE and VEGF; BTA, d-Dimer, IL6, NGAL, NSE and VEGF; BTA, CRP,IL1β, IL8, sTNFR2, vWF and FAS; d-Dimer, IL4, IL6, MMP9, NSE, VEGF andCK18; BTA, CRP, IL1α, IL2, sTNFR2, vWF and FAS; IL6, IL8, NGAL, TPSA andVEGF; FPSA, NGAL, TM, TNFα and VEGF; IL1β, IL2, NGAL, TM and VEGF; IL1α,MCP1, MMP9NGAL, NGAL, TM and TNFα; CEA, FPSA, IL8, NGAL, TM and VEGF;FPSA, IL4, NGAL, NSE, TNFα and VEGF; FPSA, IL1β, IL10, NGAL, TM, TNFαand VEGF; CEA, IL1β, IL4, NGAL, TM, TPSA and VEGF; FPSA, IL1β, IL4,IL10, NGAL, TM and VEGF; IL2, IFNγ, MCP1, MMP9NGAL and TM; IL1α, IL1β,IL6, TNFα and VEGF; IL4, IL6, IFNγ, MCP1 and TNFα; d-Dimer, IL2, IL6,MMP9NGAL, TM and TNFα; IL2, IL10, IFNγ, MCP1, MMP9NGAL and TNFα; IL6,MCP1, NGAL, NSE, TM and TNFα; d-Dimer, EGF, IL6, IL10, IFNγ, MCP1 andTNFα; d-Dimer, IL10, IFNγ, MCP1, NGAL, sTNFR1 and VEGF; or d-Dimer, IL6,IL8, IL10, NSE, TM and TNFα.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have a history of anti-cholesterol medication comprisesantibodies that bind specifically to serum CEA, urinary EGF, urinary HAand urinary CK18; serum CEA, urinary EGF, urinary IL8 and urinary CK18;serum CEA, urinary EGF, plasma IL6 and urinary MMP9NGAL; BTA, CRP, IL2,IL4 and CK18; EGF, IL1β, NGAL, VEGF and CK18; BTA, IL4, IL8, HA andCK18; EGF, CRP, IL4, VEGF, HA and CK18; EGF, IL4, IL6, IL8, vWF andCK18; BTA, EGF, IL4, IL8, HA and CK18; BTA, EGF, CRP, IL4, sTNFR1, HAand CK18; EGF, IL1α, IL1β, IL4, sTNFR1, VEGF and CK18; EGF, CRP, IL4,MMP9NGAL, NGAL, HA and CK18; CEA, FPSA, IL10, IFNγ and NGAL; CEA, IL1α,IL1β, MMP9NGAL and sTNFR1; CEA, IL1α, MMP9NGAL, TM and TNFα; CEA, IL1α,IL1β, IL6, NGAL and NSE; CEA, IL4, IL6, IL8, MMP9NGAL and TNFα; CEA,d-Dimer, IL1α, IL4, IL6 and sTNFR1; CEA, IL1α, IL4, IL6, IL8, TM andsTNFR1; CEA, IL1α, IL1β, IL4, IL8, MMP9NGAL and VEGF; CEA, IL1α, IL4,IL10, MMP9NGAL, TM and TNFα; IL1α, IL8, MMP9NGAL, NGAL and sTNFR1; IL1α,IL1β, IL4, IFNγ and psTNFR1; IL1α, IL1β, IL8, TM and psTNFR1; d-Dimer,IL1α, IL4, IL10, MMP9NGAL and TNFα; CRP, IL8, IL10, MMP9NGAL, TM andsTNFR1; d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1; IL1β, IL6, IL8,MMP9NGAL, sTNFR1, TNFα and VEGF; d-Dimer, IL1α, IL4, IL8, NGAL, TM andsTNFR1; or IL1α, IL1β, IL4, IL6, IL8, MMP9NGAL and sTNFR1.

The solid state devices for diagnosis of urothelial cancer in a subjectthat has proteinuria comprises antibodies that bind specifically toserum CEA, plasma CRP, urinary IL8 and plasma TNFα; urinary EGF, urinaryIL1β, serum IL6 and urinary vWF; serum CEA, plasma IL1α, urinary NSE andserum NSE; EGF, IL2, NSE, TM and CK18; EGF, IL6, sTNFR1, HA and CK18;EGF, NGAL, vWF, HA and CK18; EGF, IL8, sTNFR2, VEGF, uvWF and HA; EGF,IL1α, MMP9, NSE, uvWF and HA; EGF, CRP, IL2, IL4, TM and CK18; EGF,IL1β, IL2, NSE, TM, VEGF and vWF; EGF, IL1β, MMP9, MMP9NGAL, TNFα, vWFand HA; EGF, IL2, IL4, NGAL, NSE, TM and CK18; CEA, IL8, IL10, NSE andTNFα; CEA, IL2, IL8, MMP9NGAL and NSE; CEA, IL2, IL6, IL10 and NSE; CEA,IL1β, IL2, IL8, IL10 and NSE; CEA, IL1β, IL2, IL8, NSE and TPSA; CEA,CRP, IL10, MMP9NGAL, NGAL and VEGF; CEA, IL1β, IL2, IL4, IL8, NSE andTNFα; CEA, EGF, IL4, IL8, IL10, TPSA and VEGF; CEA, IL1β, IL2, IL4,IL10, MMP9NGAL and TM; CRP, IL1α, IL8, IFNγ, TM; CRP, IL1α, IL8, IFNγ,NGAL; IL1α, IL2, IL8, MCP1, TM; EGF, IL1α, IL4, IL8, IFNγ, TM; d-Dimer,IL1α, IL8, IFNγ, MCP1, TM; IL1α, IL8, IFNγ, MCP1, TM, TNFα; IL1α, IL2,IL8, IL10, IFNγ, MCP1, TM; IL1α, IL2, IL8, IFNγ, MCP1, MMP9NGAL, TM; orEGF, CRP, IL1α, IL4, IL8, IFNγ, TNFα.

The solid state devices for diagnosis of urothelial cancer in a subjectthat does not have proteinuria comprises antibodies that bindspecifically to urinary BTA, urinary NGAL, serum NGAL and urinary TNFα;urinary d-Dimer, urinary CRP, urinary NGAL and serum TNFα; serum CEA,urinary CRP, plasma MMP9NGAL and urinary NGAL; d-Dimer, CRP, IL4, NGALand sTNFR2; CRP, MMP9NGAL, NGAL, sTNFR2 and VEGF; BTA, CRP, IL4, NGALand sTNFR2; CRP, MCP1, MMP9, NGAL, sTNFR2 and VEGF; d-Dimer, CRP, IL2,IL4, NGAL and sTNFR; BTA, CRP, IL2, NGAL, sTNFR2 and vWF; d-Dimer, CRP,IL1α, IL4, MMP9NGAL, TM and CK18; BTA, EGF, CRP, MMP9, NGAL, vWF andFAS; BTA, CRP, NGAL, NSE, TM, sTNFR2 and vWF; FPSA, IL1α, IL4, IFNγ andNGAL; d-Dimer, IL2, IL4, NGAL and TM; d-Dimer, IL6, NGAL, TM and sTNFR1;d-Dimer, IL1β, IL8, NGAL, TM and TNFα; CEA, IL4, IL8, NGAL, TNFα andTPSA; d-Dimer, FPSA, IL2, IL6, IL8 and NGAL; FPSA, CRP, IL2, IL6, NGAL,TNFα and VEGF; CEA, FPSA, CRP, IL6, IL10, NGAL and VEGF; d-Dimer, FPSA,IL1β, IFNγ, MMP9NGAL, NGAL and TM; d-Dimer, IL4, MCP1, MMP9NGAL andTNFα; EGF, IL1α, IL2, MMP9NGAL and NGAL; d-Dimer, IL4, MCP1, MMP9NGALand sTNFR1; d-Dimer, IL1β, IL4, IL8, IL10 and MMP9NGAL; d-Dimer, EGF,IL8, IL10, MMP9NGAL and TM; d-Dimer, EGF, IFNγ, MMP9NGAL, NSE and VEGF;EGF, IL1α, IL2, IL4, MCP1, MMP9NGAL and NGAL; d-Dimer, EGF, CRP, IL8,MMP9NGAL, NSE and VEGF; or d-Dimer, EGF, IL1β, IL8, IL10, MMP9NGAL andVEGF.

The method of the invention may be carried out two or more times foreach individual subject by selecting two or more sub-population groupsappropriate to the subject and determining the level of one or morebiomarkers selected according to the sub-population groups.

In the context of the methods of the invention, a “control” or “controlvalue” is understood to mean the level of a particular biomarkertypically found in patients who do not have urothelial cancer. Thecontrol level of a biomarker may be determined by analysis of a sampleisolated from a person with haematuria but who does not have urothelialcancer or may be the level of the biomarker understood by the skilledperson to be typical for such a person. The control value of a biomarkermay be determined by methods known in the art and normal values for abiomarker may be referenced from the literature from the manufacturer ofan assay used to determine the biomarker level.

A number of biomarkers present in a sample isolated from a patienthaving urothelial cancer may have levels which are different to that ofa control. However, the levels of some of the biomarkers that aredifferent compared to a control may not show a strong enough correlationwith urothelial cancer such that they may be used to diagnose urothelialcancer with an acceptable accuracy.

The invention is further described with reference to the followingnon-limiting examples:

EXAMPLES

The present inventors analysed data from 156 patients recruited to acase control study to identify characteristics associated withmisclassification of diagnosis of urothelial cancer (UC). First, UCdiagnostic classifiers for 16 stratified subpopulations were defined.Second, based on 29 biomarkers measured in urine, serum and plasma, arandom forest classification was undertaken. Using random sub-samplingto generate 1000 training and test patient datasets, the probabilitiesof correct, incorrect and inconsistent classification for each patientwere estimated. Third, the distribution of patient characteristics wasexplored by using Fisher's exact tests and by defining classifiers forcontrol and UC classified subpopulations.

Patient Information and Samples

Patients

One hundred and eighty-one patients were recruited to a case controlstudy between November 2006 and October 2008 following written informedconsent. The study had ethical approval from the Office for ResearchEthics Committees Northern Ireland (ORECNI 80/04) and hospital reviewboards and was conducted according to STARD guidelines [2]. We adopted acase control study design in order to recruit sufficient numbers of UCsto ensure that the classifier did not generate a large number of falsepositives; and similarly, we recruited sufficient numbers of controlpatients to ensure that the classifier had high sensitivity. At the timeof recruitment, demographic details, medications and occupations wererecorded from each patient. We classified each patient's occupationalrisk score as low, moderate or high [2]. Patients with low occupationalrisk scores who had no known exposure to chemicals were compared topatients with moderate or high occupational risk scores or past exposureto chemicals. Final diagnosis for each patient was determinedapproximately six months after recruitment following review of eachpatient's notes. We excluded 19 patients with a history of UC who weredisease-free at the time of recruitment, one with adenocarcinoma, onewith squamous cell carcinoma, three aged>85 years, and one withinsufficient samples prior to our statistical analyses. A cohort of 156patients remained for our analyses; 80 patients with pathologicallyproven UC and 76 controls. Cytology reports were available for 64controls and 75 UCs.

Biomarkers and Analyses

Twenty-six protein biomarkers were measured in triplicate in urine (u),serum (s) and plasma (p) for each patient; three additional biomarkerswere measured in urine as single measures. We also measured creatinine,total protein and osmolality in triplicate in urine from each patient.Scientists, blinded to all patient information, analyzed the anonymizedsamples using biochip array technology [14] or ELISAs as previouslydescribed [2]. Missing values were imputed using the median value fromthe available measurements for each individual biomarker (Table 3).

Statistical Analyses—Stratified Subpopulation Classifiers

It was hypothesized that a stratified subpopulation with lowinter-patient heterogeneity, concomitant with a low level of confoundingvariables could achieve a UC diagnostic classifier with higher accuracythan a subpopulation with high inter-patient heterogeneity.

The 156 patients were stratified into 16 subpopulations using variableswhich, when split into two subpopulations, each contained >50 patients.For each subpopulation we conducted an exhaustive search of sets of fourbiomarkers (814,385 classifiers based on 68 measurements), using alogistic regression classification to define UC diagnostic classifiers[15]. The performance of each classifier was assessed using the averageArea Under the Curve (AUC) measure [16] and standard deviation (sd) froma repeated random sub-sampling analyses.

Identification of Top Ranked Biomarkers/Variables in DiagnosticClassifiers

Because we performed exhaustive searches, we identified multipleclassifiers with a similar accuracy. The top-ranked biomarkers orcategorical variables following each classification analysis wereidentified on the basis of their hypergeometric distribution:

$\begin{matrix}{{P\left( {x = a} \right)} = \frac{\begin{pmatrix}k \\a\end{pmatrix}\begin{pmatrix}{N - k} \\b\end{pmatrix}}{\begin{pmatrix}N \\m\end{pmatrix}}} & (1)\end{matrix}$

For the stratified analysis the variable “a” denotes the count frequencyof a biomarker i being present among the top-ranked 50 classifiers and“b” in the remaining classifiers. “m” is the total count frequency of abiomarker i among all classifiers. “k” denotes the total count frequencyof all biomarkers in the 50 top-ranked classifiers. “N” denotes thetotal count frequency of all biomarkers among all classifiers. For theenrichment test we used a significance level of α=0.05 and consideredmultiple testing using Bonferroni.

Statistical Analyses—Supervised Patient Classification Analysis

For the patient dataset L=L₁, . . . , L_(w) with “w” patients and “m”biomarker measurements we used a repeated random sub-sampling for thegeneration of n=1000 pairs of training and test datasets. For eachtraining dataset, which comprised 70% of the 156 patients, a randomforest UC diagnostic classifier was generated using all the biomarkermeasurements (Table 3). This classifier was subsequently validated usingthe corresponding test dataset based on the remaining 30% of the 156patients (FIG. 1). The random forest classification was performed usingthe R package random forest [17].

For each patient L_(i) we determined the count frequencies that theywere correctly, incorrectly or inconsistently classified across all testdatasets. For each patient we tested two null-hypotheses: (1) that theywere not more often correctly classified than expected by random chanceH₀ ¹); and (2) not more often incorrectly classified than expected byrandom chance (H₀ ²). The probability to reject the null hypothesis wasestimated by the hypergeometric distribution (eq. 1).

For the n=1000 random sub-sampled test datasets each consisting of 30%of the patients (47 patients), a total of N=47,000 predictions wereperformed. For testing H₀ ¹, “a” denotes the frequency that a patientL_(i) was classified correctly, “k” the total number of correctclassifications for all patients, “m” the frequency a patient L_(i) wassampled in “n” test datasets and b=m−a. For testing H₀ ², “a” denotesthe frequency how often a patient L_(i) was classified falsely, “k” thetotal number of false classifications for all patients. For both testswe used a significance level α=0.05 and applied multiple hypothesistesting adjustments using the false discovery rate (FDR)[18]. Wedesignated the subpopulation that rejected H₀ ¹ as classifiable, thesubpopulation that rejected H₀ ² as non-classifiable, and asubpopulation that rejected neither H₀ ¹ and H₀ ² as inconsistent.

We then performed exhaustive searches of sets of five categoricalvariables (575,757 classifiers based on 39 variables) to determine UCdiagnostic classifiers for the classifiable and non-classifiablesubpopulations as previously described for the stratified subpopulationdiagnostic classifiers.

Comparison of Characteristics Across Classifiable and Non-ClassifiableSubpopulations

We performed a Fisher's exact test to compare the distribution ofcharacteristics across the following classifiable and non-classifiablepatient subpopulations: classifiable and non-classifiable controlpatients; classifiable and non-classifiable UC patients; classifiablecontrols and non-classifiable UC patients and; classifiable UC andnon-classifiable control patients, applying multiple hypotheses testingadjustments using the FDR as appropriate [18].

Results and Discussion

UC Diagnostic Classifiers for Stratified Sub-Populations

The classifier for the non-smoker subpopulation significantlyoutperformed the classification performance of all other subpopulationsachieving AUC>0.95 (sd=0.10). Carcino-embryonic antigen (CEA) acted as acentral protein biomarker with links to 11 stratified subpopulations(FIG. 2; Table 1).

The poor performances of the classifiers for the smoking and >65 yearsstratified patient subpopulations (Table 1), indicate that smoking andincreased age confound UC diagnostic classifiers. The bestclassification performances across stratified subpopulations wereachieved for the subpopulation composed of non-smokers (FIG. 2)suggesting that non-smokers were the most homogeneous subpopulation.

We observed that biomarkers in diagnostic classifiers were highlyredundant resulting in multiple classifiers that achieved similaraccuracies. Urine biomarkers were omnipresent in the best performingdiagnostic classifiers supporting the concept that protein secretionsfrom tumor and urothelial cells into urine, accurately reflect thestatus of the urothelium, both in the absence and/or presence of UC, ina way that captures the complexities of the disease status of individualpatients [19]. Contrary to commonly applied heuristic approaches, weapplied an exhaustive search of all biomarker measurements, meaning thatevery possible combination of biomarkers was assessed, in comparison toa feature selection method that searches only a subspace thereof.

The top performing combinations of 5, 6 and 7 biomarkers in urine, serumand plasma were identified for each subpopulation of the testpopulation. These combinations (classifiers) are presented below inTables 4 to 12. Table 4 provides the best performing combinations of 5biomarkers measured in urine for each of the subpopulations based onsubjects history of smoking, age, history of anti-hypertensivemedication, history of anti-cholesterol medication, history of exposureto occupational risks or hazardous chemicals, history of alcoholconsumption, cytological detection of inflammatory cells andproteinuria. Tables 7 and 10 respectively provide the best performingcombinations of 6 and 7 biomarkers measured in urine for each of thesame subpopulations. Tables 5, 8 and 11 respectively provide the bestperforming combinations of 5, 6 and 7 biomarkers measured in serum foreach of the same subpopulations. Tables 6, 9 and 12 respectively providethe best performing combinations of 5, 6 and 7 biomarkers measured inplasma for each of the same subpopulations.

For each combination of 5, 6 or 7 biomarkers identified in tables 4 to12, the skilled person would appreciate that the level of eachindividual biomarker can be altered in a sample independently of theother biomarkers in the same combination. The individual biomarkersidentified by the present inventors as having an altered level insubjects suffering from or having increased risk of urothelial cancercompared to a control value are BTA, CEA, CK18, CRP, Creatinine, dDimer, EGF, FAS, HA, IL1α, IL1β, IL2, IL4, IL6, IL8, IL10, IFNγ, MCP1,MMP9, NGAL, MMP9NGAL complex, NSE, FPSA, TPSA, TM, TNFα, sTNFR1, sTNFR2,VEGF and vWF. These biomarkers were identified by statistical analysisbased on diagnostic algorithms across demographic variables whichinclude one or more of the patient's smoking history, age, history ofanti-hypertension medication, history of anti-cholesterol medication,history of alcohol consumption, history of exposure to occupationalrisks or hazardous chemicals, proteinuria and cytological detection ofinflammatory cells. Relevant demographic variables for each patient maybe assigned a notional value on the basis of predicted probability (PP)on the basis of Forward Wald binary logistic regression analyses. PPrepresents, in a single measure, the intrinsic contribution toward groupmembership (urothelial cancer or control) with which each subjectcommences screening. The contribution that each biomarker makes to thearea under the curve (AUC) values for each PP can be assessed todetermine whether a combination of biomarkers increases PP for thatpatient.

For exemplary purposes the alterations in the levels of biomarkers inthe combinations of 7 biomarkers in samples from healthy subjectsrelative to those from urothelial cancer patients are indicated inTables 13 to 15. In Table 13 it can be seen how individual biomarkerlevels in 7 biomarker combinations are altered in urine from healthysubjects compared to urine from UC patients. In Table 14 it can be seenhow individual biomarker levels in 7 biomarker combinations are alteredin serum from healthy subjects compared to serum from UC patients. InTable 15 it can be seen how individual biomarker levels in 7 biomarkercombinations are altered in plasma from healthy subjects compared toplasma from UC patients.

For exemplary purposes the alterations in the levels of biomarkers inthe combinations of 7 biomarkers in samples from UC patients relative tothose from healthy subjects are indicated in Tables 16 to 18. In Table16 it can be seen how individual biomarker levels in 7 biomarkercombinations are altered in urine from UC patients compared to urinefrom healthy subjects. In Table 17 it can be seen how individualbiomarker levels in 7 biomarker combinations are altered in serum fromUC patients compared to serum from healthy subjects. In Table 18 it canbe seen how individual biomarker levels in 7 biomarker combinations arealtered in plasma from UC patients compared to plasma from healthysubjects.

Supervised Classification Analyses

One hundred of the 156 (64%) patients were classified correctly(controls (n=46) (FIG. 3A), UC (n=54) (FIG. 3B)); 46/156 (30%) werenon-classifiable (controls (n=23), UC (n=23)); and 10/156 (6%) wereinconsistently classified (controls (n=7), UC (n=3)) (FIGS. 3A and B).The 54 patients with UC who were correctly classified had CIS (n=1),pTaG1 (n=2), pTaG2 (n=17), pTaG3 (n=5), pT1G2 (n=3), pT1G3 (n=8), pT2aG2(n=1), pT2aG3 (n=9), pT2bG3 (n=2), pT3aG3 (n=1), pT3bG3 (n=3), andpT4aG3 (n=2); the 23 who were non-classifiable had pTaG1 (n=2), pTaG2(n=16), pTaG3 (n=3), pT1 G3 (n=1), and CIS (n=1). Two patients withpTaG3 disease and one with pT1 G3 were inconsistently classified. Threepatients with renal cancer and two with prostate cancer were classifiedas UC; one patient with prostate cancer was inconsistently classified(FIG. 3A).

Characteristics of Classifiable and Non-Classifiable PatientSubpopulations

Interestingly, age, smoking years and anti-hypertensive medication werethe top-ranked contributors to the most accurate diagnostic classifiersfor the subpopulation of patients classified as controls (Table 2A). Incomparison to classifiable control patients, non-classifiable controlpatients were more likely to be dipstick positive for white blood cells,to have inflammatory cells in their urine, to have abnormal cytology andto be dipstick positive for blood (FIG. 3A). Interestingly, 65/80 (81%)patients with pathologically proven UC and 48/76 (61%) of the controlshad visible hematuria [2].

The patients misclassified as “controls” could have had unidentified UC.Nine of the 36 patients with a final diagnosis “no diagnosis” werenon-classifiable or inconsistently classified (FIG. 3A). Undetected UCis now an accepted challenge [20], but, because we do not yet know theproportion of anticipatory controls, it is not possible to introducemethodologies to adjust for their existence when we are measuring theaccuracy of diagnostic classifiers [21]. This highlights that accurateclinical final diagnoses may only be possible after several yearsfollow-up.

Non-classifiable UC patients were more likely than classifiable UCpatients to be dipstick negative for blood and protein, to have lowstage UC (FIG. 3B). Non classifiable UC patients were more likely thanclassifiable controls to be taking anti-hypertensives (AH) and to beheavy smokers (FIG. 3C). Patients correctly classified as UC werepredominantly high grade/stage UCs; a proportion of the controls,classified as UC, had serious diagnoses, including cancers other thanbladder cancer (FIG. 4A). Age, cigarettes/day, history of BPE, diureticmedication and anti-hypertensive medication frequently contributed tothe diagnostic classifier for the subpopulation classified as UC (Table2B). The latter variables thus discriminated the misclassified controlsfrom the classifiable UCs.

There was no significant heterogeneity across the classifiable UC andnon-classifiable control patients.

From our finding that age and smoking years were the top-rankedvariables which contributed to the UC diagnostic classifiers forpatients classified as controls, we extrapolated that smoking and age>65years might discriminate the misclassified UC from the classifiablecontrols. Indeed, 22 of the 23 non-classifiable UC patients weresmokers, >65 years or smokers>65 years (FIG. 4B). The remaining patienthad pTa disease concomitant with stone disease which may have confoundedclassification (FIG. 4B). Eighteen of the 46 patients who wereclassified as controls did not smoke and were aged≤65 years. Thesepatients had low risk diagnoses; no diagnosis (n=12), renal trauma(n=1), stones (n=3), urinary tract infection (n=1), BPE and stone (n=1)(FIG. 4B).

Diagnostic Classifiers for the Identification of Low Risk Subpopulations

We have demonstrated that the most accurate classification was achievedfor younger non-smokers. Young smokers with micro hematuria could beprioritised for screening using biochips formatted with antibodies tothe proteins contributing to diagnostic classifiers [14]. Oncevalidated, biochip screening could replace cystoscopy for these low-riskpatients, thus reducing healthcare costs.

We have conducted the first systematic investigation of the pathologiesand patient characteristics underlying the failure of diagnosticclassifiers for patients with hematuria. Although the biomarkers andpatients are specific to our study, our novel approach and analysescould be applied to identify confounding factors for diagnosticclassifiers in other complex diseases.

TABLE 1 UC diagnostic classifiers for stratified subpopulations.Population set Biomarker TP FP FN TN AUC non smoker 1 s-CEA, u-EGF,p-IL8, u-CK18 1.84 (0.37) 0.08 (0.28) 0.16 (0.37) 2.92 (0.28) 0.95(0.1)  non smoker 2 s-CEA, p-IL8, s-NGAL, s-TM 1.76 (0.44) 0.04 (0.20)0.24 (0.44) 2.96 (0.20) 0.93 (0.11) non smoker 3 s-CEA, p-IL8, s-NGAL,p-NSE 1.84 (0.37) 0.20 (0.41) 0.16 (0.37) 2.80 (0.41) 0.93 (0.12) AC yes1 s-MCP1, p-MCP1, s-NGAL, p-NGAL 2.56 (0.65) 0.12 (0.33) 0.44 (0.65)1.88 (0.33)  0.9 (0.14) AC yes 2 u-CRP, s-IL2, s-NGAL, p-NGAL 2.64(0.49) 0.20 (0.50) 0.36 (0.49) 1.80 (0.50) 0.89 (0.16) AC yes 3 u-Creat,s-NGAL, p-NGAL, p-VEGF 2.80 (0.41) 0.36 (0.57) 0.20 (0.41) 1.64 (0.57)0.88 (0.16) OCR yes 1 s-CEA, u-EGF, u-VEGF, u-vWF 3.52 (0.59) 0.32(0.48) 0.48 (0.59) 2.68 (0.48) 0.89 (0.1)  OCR yes 2 u-EGF, s-IL8,u-vWF, u-HA 3.48 (0.65) 0.36 (0.57) 0.52 (0.65) 2.64 (0.57) 0.88 (0.14)OCR yes 3 s-IL4, p-IL8, s-MCP1, u-VEGF 3.08 (0.91) 0.08 (0.28) 0.92(0.91) 2.92 (0.28) 0.87 (0.12) age ≤ 65 1 s-CEA, u-EGF, s-IL1α, u-VEGF2.48 (0.65) 0.28 (0.46) 0.52 (0.65) 4.72 (0.46) 0.89 (0.12) age ≤ 65 2s-CEA, u-CRP, s-IL1α, u-VEGF 2.40 (0.87) 0.28 (0.46) 0.60 (0.87) 4.72(0.46) 0.87 (0.14) age ≤ 65 3 s-CEA, s-IL1α, p-IFN-γ, u-VEGF 2.32 (0.85)0.16 (0.37) 0.68 (0.85) 4.84 (0.37) 0.87 (0.14) CI no 1 s-CEA, p-IL8,s-TNFα, u-FAS 1.68 (0.56) 0.44 (0.85) 0.32 (0.56) 3.56 (0.65) 0.86(0.17) CI no 2 u-EGF, s-EGF, s-FPSA, s-IL4 1.68 (0.63) 0.56 (0.82) 0.32(0.63) 3.44 (0.82) 0.85 (0.15) CI no 3 u-EGF, u-CRP, u-IL4, u-NSE 1.52(0.65) 0.24 (0.52) 0.48 (0.65) 3.76 (0.52) 0.85 (0.18) AC no 1 s-CEA,u-EGF, u-HA, u-CK18 4.28 (0.74) 0.84 (0.94) 0.72 (0.74) 5.16 (0.94) 0.86(0.12) AC no 2 s-CEA, u-EGF, u-IL8, u-CK18 4.20 (0.76) 0.80 (0.87) 0.80(0.76) 5.20 (0.87) 0.85 (0.11) AC no 3 s-CEA, u-EGF, p-IL6, u-MMP9NGAL4.04 (0.89) 0.68 (0.90) 0.96 (0.89) 5.32 (0.90) 0.85 (0.11) AH no 1s-CEA, u-CRP, u-NSE, s-TNFα 2.32 (0.69) 0.32 (0.56) 0.68 (0.69) 4.68(0.56) 0.85 (0.13) AH no 2 s-CEA, u-CRP, s-IL4, u-sTNFR 2.32 (0.69) 0.64(0.7)  0.68 (0.69) 4.36 (0.70) 0.82 (0.12) AH no 3 u-Creat, s-IL6,p-MMP9NGAL, u- 2.00 (0.87) 0.12 (0.33) 1.00 (0.87) 4.88 (0.33) 0.82(0.14) VEGF OCR no 1 s-CEA, s-dDimer, u-EGF, s-IL1α 3.16 (0.9)  0.48(0.59) 0.84 (0.9)  3.52 (0.59) 0.84 (0.14) OCR no 2 s-CEA, s-dDimer,s-IL6, s-MCP1 3.00 (0.71) 0.36 (0.57) 1.00 (0.71) 3.64 (0.57) 0.83(0.11) OCR no 3 u-BTA, s-CEA, u-TNFα, u-CK18 3.12 (0.88) 0.52 (0.71)0.88 (0.88) 3.48 (0.71) 0.82 (0.10) protein yes 1 s-CEA, p-CRP, u-IL8,p-TNFα 4.80 (0.41) 0.56 (0.58) 0.20 (0.41) 1.44 (0.58) 0.84 (0.15)protein yes 2 u-EGF, u-IL1β, s-IL6, u-vWF 4.44 (0.71) 0.44 (0.51) 0.56(0.71) 1.56 (0.51) 0.83 (0.14) protein yes 3 s-CEA, p-IL1α, u-NSE, s-NSE4.68 (0.56) 0.56 (0.51) 0.32 (0.56) 1.44 (0.51) 0.83 (0.13) alcohol no 1s-MMPNG, s-sTNFR, s-TNFα, u- 3.44 (0.71) 0.56 (0.58) 0.56 (0.71) 2.44(0.58) 0.84 (0.13) VEGF alcohol no 2 s-CEA, u-EGF, s-IL10, s-NGAL 3.36(0.64) 0.52 (0.59) 0.64 (0.64) 2.48 (0.59) 0.83 (0.15) alcohol no 3u-IL6, p-MMP9NGAL, u-VEGF, u- 3.52 (0.51) 0.64 (0.76) 0.48 (0.51) 2.36(0.76) 0.83 (0.14) CK18 alcohol yes 1 u-EGF, u-IL1β, s-MMP9NGAL, u- 3.48(0.82) 1.08 (0.95) 0.52 (0.82) 3.92 (0.95) 0.83 (0.11) vWF alcohol yes 2s-CEA, u-EGF, u-vWF, u-CK18 3.16 (1.03) 0.72 (0.61) 0.84 (1.03) 4.28(0.61) 0.82 (0.13) alcohol yes 3 s-CEA, u-EGF, p-NSE, u-vWF 3.28 (074) 0.92 (0.95) 0.72 (0.74) 4.08 (0.95) 0.82 (0.13) protein no 1 u-BTA,u-NGAL, s-NGAL, u-TNFα 2.12 (0.67) 0.32 (0.56) 0.88 (0.67) 4.68 (0.56)0.82 (0.11) protein no 2 u-dDimer, u-CRP, u-NGAL, s-TNFα 2.24 (0.78) 0.6 (0.87) 0.76 (0.78)  4.4 (0.87) 0.81 (0.14) protein no 3 s-CEA,u-CRP, P-MMP9NGAL, u- 2.28 (0.74) 0.76 (0.72) 0.72 (0.74) 4.24 (0.72) 0.8 (0.14) NGAL age > 65 1 s-IL2, s-MMP9NGAL, s-NGAL, p- 4.40 (0.87)0.72 (0.68)  0.6 (0.87) 2.28 (0.68) 0.82 (0.16) sTNFR age > 65 2u-MMP9NGAL, s-NGAL, p-NGAL, u- 4.32 (0.75) 0.72 (0.79) 0.68 (0.75) 2.28(0.79) 0.81 (0.15) vWF age > 65 3 s-CEA, s-dDimer, p-dDimer, s-Ifn-γ4.40 (0.82) 0.80 (0.76) 0.60 (0.82) 2.20 (0.76) 0.81 (0.15) AH yes 1u-EGF, u-IL1α, s-IL10, u-vWF 4.88 (0.33) 0.68 (0.63) 0.12 (0.33) 1.32(0.63) 0.82 (0.16) AH yes 2 u-EGF, p-IL10, u-VEGF, u-vWF 4.84 (0.37)0.68 (0.69) 0.16 (0.37) 1.32 (0.69) 0.81 (0.17) AH yes 3 s-sTNFR,p-sTNFR, s-TNFα, u-vWF 4.40 (0.65) 0.52 (0.65)  0.6 (0.65) 1.48 (0.65)0.81 (0.19) CI yes 1 u-BTA, s-CEA, p-IL10, u-CK18 4.72 (0.46) 1.00(0.76) 0.28 (0.46) 2.00 (0.76) 0.81 (0.13) CI yes 2 u-BTA, p-IL6, s-NSE,p-NSE 4.72 (0.46) 1.04 (0.84) 0.28 (0.46) 1.96 (0.84) 0.80 (0.15) CI yes3 u-protein, u-BTA, p-IL6, s-NGAL 4.44 (0.82) 0.92 (0.57) 0.56 (0.82)2.08 (0.57) 0.79 (0.13) smoker 1 u-EGF, u-IL6, u-VEGF, u-CK18 5.52(0.65) 1.32 (0.75) 0.48 (0.65) 2.68 (0.75) 0.80 (0.10) smoker 2 u-EGF,s-IL8, u-vWF, u-FAS 5.40 (0.76) 1.28 (0.98)  0.60 (0.760) 2.72 (0.98)0.79 (0.13) smoker 3 u-EGF, u-IL1α, p-MMP9NGAL, u- 5.44 (0.65) 1.44(0.92) 0.56 (0.65) 2.56 (0.92) 0.77 (0.13) vWF Table 1: UC diagnosticclassifiers for stratified subpopulations. Patients were stratified intosubpopulations when variables contained >50 patients in eachsubpopulation. Patients were split according to smoking, anticholesterol (AC) medication, occupational risk or chemical exposure(OCC), age, cytology with inflammatory cells (CI), anti-hypertensive(AH) medication, dip stick protein and alcohol. The diagnosticclassifiers with the three highest AUCs are shown. TP = total positives,FP = false positives, FN = false negatives, TN = true negatives, u- =urine, s- = serum, p- = plasma, BTA = Bladder Tumor Antigen, CEA =Carcinoembryonic antigen, CK18 = Human cytokeratin 18, CRP = C-reactiveprotein, EGF = Epidermal Growth Factor, HA = Hyaluronidase, Ifn-γ =Interferon-γ , MCP-1 = Monocyte chemoattractant protein 1, MMP9 = Matrixmetalloproteinase 9, MMP9NGAL complex, NGAL = Neutrophilgelatinase-associated lipocalin, NSE = Neurone Specific Enolase, PSA =Prostate specific antigen, TM = Thrombomodulin, TNFα = Tumor necrosisfactor α, VEGF = Vascular endothelial growth factor, vWF = vonWillebrand Factor.

TABLE 2 UC diagnostic classifiers based on categorical variables for thecontrol and UC classified subpopulations. Variables TP FP FN TN AUC A) 1age, smoking years, 2.52 0.52 0.48 4.48 0.87 history stone disease,(0.59) (0.71) (0.59) (0.71) (0.15) alpha blockers, beta 2 age, smoking,alpha 2.52 0.72 0.48 4.28 0.85 blockers, anti- (0.59) (0.89) (0.59)(0.89) (0.13) cholesterol, 3 age, smoking, alpha 2.32 0.40 0.68 4.600.85 blockers, (0.8) (0.58) (0.8) (0.58) (0.14) antidepressants,dipstick protein B) 1 age, cigarettes/day, 4.56 0.96 0.44 2.04 0.80history benign prostate (0.58) (0.89) (0.58) (0.89) (0.14) enlargement,diuretic medication, anti- hypertensive medications 2 age, cigarettesper 4.60 1.04 0.40 1.96 0.79 day, history benign (0.58) (0.68) (0.58)(0.68) (0.1) prostate enlargement, history of malignancy,anti-hypertensive medications 3 age, cigarettes/day, 4.60 1.04 0.40 1.960.79 history BPE, diuretic (0.5) (0.98) (0.5) (0.98) (0.18) medication,anti- inflammatories Table 2: UC diagnostic classifiers based oncategorical variables for the control and UC classified subpopulations.Diagnostic classifiers for the control classified (A) and UC classified(B) subpopulations, TP = total positives, FP = false positives, FN =false negatives, TN = true negatives, AUC = area under the curve.

TABLE 3 Overview of protein biomarkers. The missing data column showsthe number of patients with missing values. Biomarker SensitivityMissing data Bladder Tumor Antigen (BTA) 0.65 U/ml u (0)Carcino-embryonic antigen (CEA) 0.29 ng/mL s (0) Human cytokeratin 18(CK18) 0.12 ng/mL u (2) C-reactive protein (CRP) 0.67 ng/mL u (0), s(25), p (21) d-Dimer 2.10 ng/mL u (0), s (21), p (0) Epidermal GrowthFactor (EGF) 2.90 ng/mL u (2), s (28), p (0) FAS 5.00 ng/mL u (2)Hyaluronidase (HA) 25.00 ng/mL u (2) IL1α 0.80 pg/mL u (1), s (8), p (0)IL1β 1.60 pg/mL u (1), s (8), p (0) IL2 4.80 pg/mL u (1), s (8), p (0)IL4 6.60 pg/mL u (0), s (30), p (42) IL6 1.20 pg/mL u (0), s (8), p (0)IL8 7.90 pg/mL u (1), s (47), p (0) IL10 1.10 pg/mL s (8), p (0)Interferon-γ (Inf-γ) 0.44 pg/ml s (8), p (0) Monocyte chemoattractantprotein 1/(MCP-1) 13.20 pg/mL u (1), s (8), p (0) Matrixmetalloproteinase 9 (MMP9) 3.03 ng/mL u (1) MMP9-NGAL complex N/A u (5),s(2), p(3) NGAL (Neutrophil gelatinase-associated lipocalin) 17.80 ng/mLu (0), s (21), p (0) Neurone Specific Enolase (NSE), γ-enolase 0.26ng/mL u (0), s (21), p (0) Prostate specific antigen (PSA) (free) 0.02ng/ml s (0) Prostate specific antigen (PSA) (total) 0.45 ng/ml s (0)Thrombomodulin (TM) 0.50 ng/mL u (0), s (21), p (0) Tumor necrosisfactor α (TNFα) 4.40 pg/mL u (1), s (8), p (0) sTNFR1 0.24 ng/ml u (0),s (21), p(0) sTNFR2 0.20 ng/ml u (1) Vascular endothelial growth factor(VEGF) 14.60 pg/mL u (1), s (8), p (0) von Willebrand Factor (vWF) 1U/ml u (8) protein N/A u (0) creatinine N/A u (0) osmolality N/A u (0)

TABLE 4 Urine 5 biomarker classifiers name num Biomarker TP FP FN TN AUCsmoking 1 u-BTA, u-MMP9NG, u-TM, 1.6 (0.65) 0.12 (0.33) 0.4 (0.65) 2.88(0.33) 0.88 (0.17) no u-sTNFR2, u-VEGF smoking 2 u-BTA, u-IL4, u-MMP9,1.64 (0.49) 0.2 (0.41) 0.36 (0.49) 2.8 (0.41) 0.88 (0.14) no u-NSE,u-FAS smoking 3 u-BTA, u-MMP9NG, u-TNFa, 1.56 (0.65) 0.12 (0.33) 0.44(0.65) 2.88 (0.33) 0.87 (0.17) no u-sTNFR2, u-VEGF CI no 1 u-EGF, u-CRP,u-IL4, 1.6 (0.5) 0.2 (0.41) 0.4 (0.5) 3.8 (0.41) 0.88 (0.12) u-TM, u-vWFCI no 2 u-BTA, u-dDimer, u-EGF, 1.52 (0.65) 0.2 (0.5) 0.48 (0.65) 3.8(0.5) 0.86 (0.16) u-CRP, u-IL4 CI no 3 u-EGF, u-CRP, u-IL4, 1.64 (0.57)0.48 (0.65) 0.36 (0.57) 3.52 (0.65) 0.85 (0.18) u-IL6, u-vWF age < 65 1u-EGF, u-IL2, u-HA, 2.36 (0.86) 0.4 (0.58) 0.64 (0.86) 4.6 (0.58) 0.85(0.17) u-FAS, u-CK18 age < 65 2 u-EGF, u-IL2, u-MMP9NG, 2.4 (0.71) 0.48(0.65) 0.6 (0.71) 4.52 (0.65) 0.85 (0.15) u-HA, u-CK18 age < 65 3 u-EGF,u-vWF, u-HA, 2.24 (0.83) 0.28 (0.54) 0.76 (0.83) 4.72 (0.54) 0.85 (0.16)u-FAS, u-CK18 OCR 1 u-BTA, u-IL2, u-IL4, 2.96 (1.06) 0.12 (0.33) 1.04(1.06) 2.88 (0.33) 0.85 (0.14) yes u-MMP9NG, u-VEGF OCR 2 u-BTA, u-IL1a,u-IL8, 3 (1.04) 0.16 (0.47) 1 (1.04) 2.84 (0.47) 0.85 (0.14) yes u-NGAL,u-NSE OCR 3 u-BTA, u-CRP, u-IL4, 3.4 (0.76) 0.48 (0.65) 0.6 (0.76) 2.52(0.65) 0.84 (0.16) yes u-NSE, u-CK18 alcohol 1 u-IL2, u-IL8, u-NGAL,3.36 (0.76) 0.6 (0.58) 0.64 (0.76) 2.4 (0.58) 0.82 (0.12) no u-HA,u-CK18 alcohol 2 u-IL2, u-IL4, u-VEGF, 3.28 (0.74) 0.56 (0.65) 0.72(0.74) 2.44 (0.65) 0.82 (0.12) no u-HA, u-CK18 alcohol 3 u-IL1b, u-IL2,u-IL8, 3.24 (0.72) 0.64 (0.61) 0.76 (0.72) 2.36 (0.81) 0.8 (0.16) nou-NGAL, u-CK18 alcohol 1 u-EGF, u-MMP9, u-sTNFR2, 3.2 (0.76) 0.8 (0.71)0.8 (0.76) 4.2 (0.71) 0.82 (0.1) yes u-VEGF, u-vWF alcohol 2 u-EGF,u-IL1a, u-IL4, 3.48 (0.51) 1.24 (1.05) 0.52 (0.51) 3.76 (1.05) 0.81(0.11) yes u-vWF, u-FAS alcohol 3 u-EGF, u-IL1a, u-MMP9, 3.44 (0.65) 1.2(0.87) 0.56 (0.65) 3.8 (0.87) 0.81 (0.12) yes u-vWF, u-HA AC no 1 u-BTA,u-CRP, u-IL2, 3.64 (1.11) 0.56 (0.77) 1.36 (1.11) 5.44 (0.77) 0.82(0.11) u-IL4, u-CK18 AC no 2 u-EGF, u-IL1b, u-NGAL, 3.84 (0.94) 0.84(0.75) 1.16 (0.94) 5.16 (0.75) 0.81 (0.09) u-VEGF, u-CK18 AC no 3 u-BTA,u-IL4, u-IL8, 3.36 (1.32) 0.28 (0.54) 1.64 (1.32) 5.72 (0.54) 0.81(0.13) u-HA, u-CK18 AC yes 1 u-CRP, u-MCP1, u-sTNFR2, 2.92 (0.28) 0.68(0.63) 0.08 (0.28) 1.32 (0.63) 0.82 (0.15) u-vWF, u-FAS AC yes 2u-dDimer, u-IL6, u-MMP9NG, 2.24 (0.88) 0.24 (0.52) 0.76 (0.88) 1.76(0.52) 0.81 (0.17) u-NSE, u-VEGF AC yes 3 u-BTA, u-MCP1, u-sTNFR2, 2.8(0.41) 0.64 (0.76) 0.2 (0.41) 1.36 (0.76) 0.81 (0.18) u-vWF, u-FAS AH no1 u-CRP, u-NGAL, u-VEGF, 2.04 (0.89) 0.28 (0.54) 0.96 (0.89) 4.72 (0.54)0.81 (0.16) u-HA, u-CK18 AH no 2 u-dDimer, u-TNFa, u-VEGF, 1.92 (0.64)0.28 (0.46) 1.08 (0.64) 4.72 (0.46) 0.79 (0.12) u-HA, u-CK18 AH no 3u-MMP9, u-NSE, u-TM, 1.8 (0.71) 0.12 (0.33) 1.2 (0.71) 4.88 (0.33) 0.79(0.11) u-VEGF, u-FAS age > 65 1 u-BTA, u-IL1b, u-VEGF, 4.56 (0.58) 0.88(0.73) 0.44 (0.58) 2.12 (0.73) 0.81 (0.14) u-vWF, u-HA age > 65 2u-dDimer, u-IL1a, u-NSE, 4.4 (0.76) 1 (0.82) 0.6 (0.76) 2 (0.82) 0.77(0.17) u-vWF, u-HA age > 65 3 u-BTA, u-dDimer, u-IL1b, 4.48 (0.71) 1.08(0.95) 0.52 (0.71) 1.92 (0.95) 0.77 (0.18) u-vWF, u-HA protein 1 u-EGF,u-IL2, u-NSE, 4.56 (0.58) 0.6 (0.71) 0.44 (0.58) 1.4 (0.71) 0.81 (0.18)yes u-TM, u-CK18 protein 2 u-EGF, u-IL6, u-sTNFR, 4.36 (0.7) 0.52 (0.51)0.64 (0.7) 1.48 (0.51) 0.81 (0.14) yes u-HA, u-CK18 protein 3 u-EGF,u-NGAL, u-vWF, 4.44 (0.77) 0.64 (0.7) 0.56 (0.77) 1.36 (0.7) 0.78 (0.2)yes u-HA, u-CK18 protein 1 u-dDimer, u-CRP, u-IL4, 2.24 (0.6) 0.76(0.78) 0.76 (0.6) 4.24 (0.78) 0.8 (0.12) no u-NGAL, u-sTNFR2 protein 2u-CRP, u-MMP9NG, u-NGAL, 2.08 (0.64) 0.52 (0.51) 0.92 (0.64) 4.48 (0.51)0.79 (0.12) no u-sTNFR2, u-VEGF protein 3 u-BTA, u-CRP, u-IL4, 2 (0.82)0.4 (0.71) 1 (0.82) 4.6 (0.71) 0.79 (0.15) no u-NGAL, u-sTNFR2 smoking 1u-EGF, u-IL1b, u-sTNFR, 5.48 (0.59) 1.4 (0.87) 0.52 (0.59) 2.6 (0.87)0.78 (0.13) yes u-VEGF, u-CK18 smoking 2 u-BTA, u-EGF, u-IL1b, 5.32(0.75) 1.32 (0.95) 0.68 (0.75) 2.68 (0.95) 0.78 (0.12) yes u-vWF, u-FASsmoking 3 u-EGF, u-IL1b, u- 5.56 (0.65) 1.48 (0.87) 0.44 (0.65) 2.52(0.87) 0.78 (0.11) yes IL8, u-TM, u-vWF AH yes 1 u-CRP, u-IL2, u-IL8,4.8 (0.41) 0.8 (0.58) 0.2 (0.41) 1.2 (0.58) 0.78 (0.14) u-sTNFR2, u-vWFAH yes 2 u-EGF, u-IL8, u-NSE, 4.72 (0.68) 0.8 (0.58) 0.28 (0.68) 1.2(0.58) 0.77 (0.16) u-TNFa, u-vWF AH yes 3 u-BTA, u-EGF, u-IL4, 5 (0)0.92 (0.7) 0 (0) 1.08 (0.7) 0.77 (0.18) u-vWF, u-HA OCR no 1 u-BTA,u-TM, u-TNFa, 2.76 (0.93) 0.6 (0.82) 1.24 (0.93) 3.4 (0.82) 0.77 (0.18)u-sTNFR2, u-vWF OCR no 2 u-BTA, u-TM, u-TNFa, 2.72 (0.94) 0.56 (0.71)1.28 (0.94) 3.44 (0.71) 0.77 (0.13) u-vWF, u-FAS OCR no 3 u-EGF, u-NSE,u-TNFa, 3.08 (0.7) 0.92 (0.76) 0.92 (0.7) 3.08 (0.76) 0.77 (0.11) u-vWF,u-HA CI yes 1 u-BTA, u-IL1a, u-NGAL, 4.56 (0.51) 1.24 (0.83) 0.44 (0.51)1.76 (0.83) 0.75 (0.16) u-sTNFR, u-vWF CI yes 2 u-BTA, u-IL8, u-MMP9NG,4.32 (0.69) 1.12 (0.78) 0.68 (0.69) 1.88 (0.78) 0.75 (0.14) u-VEGF,u-CK18 CI yes 3 u-BTA, u-IL6, u-MMP9NG, 4.64 (0.64) 1.36 (0.81) 0.36(0.64) 1.64 (0.81) 0.74 (0.15) u-NSE, u-CK18

TABLE 5 Serum 5 biomarker classifiers name num Biomarker TP FP FN TN AUCsmoking 1 s-CEA, s-EGF, s-IL4, 1.8 (0.41) 0.16 (0.47) 0.2 (0.41) 2.84(0.47) 0.92 (0.12) no s-NGAL, s-TNFa smoking 2 s-CEA, s-EGF, s-IL8, 1.8(0.41) 0.16 (0.37) 0.2 (0.41) 2.84 (0.37) 0.92 (0.12) no s-NGAL, s-TPSAsmoking 3 s-CEA, s-IL8, s-MCP1, 1.8 (0.5) 0.16 (0.37) 0.2 (0.5) 2.84(0.37) 0.92 (0.13) no s-NGAL, s- age < 65 1 TPSA s-CEA, s-IL1a, s-IL4,2.28 (0.89) 0.28 (0.54) 0.72 (0.89) 4.72 (0.54) 0.85 (0.16) s-TM, s-TNFaage < 65 2 s-CEA, s-IL1a, s-IL2, 2.4 (0.71) 0.56 (0.65) 0.6 (0.71) 4.44(0.65) 0.84 (0.14) s-IL4, s-IL8 age < 65 3 s-CEA, s-IL1a, s-IL1b, 2.36(0.49) 0.76 (0.72) 0.64 (0.49) 4.24 (0.72) 0.82 (0.13) s-IL4, s-VEGF ACno 1 s-CEA, s-FPSA, s-IL10, 3.88 (1.05) 0.68 (0.63) 1.12 (1.05) 5.32(0.63) 0.83 (0.1) s-Ifngg, s-NGAL AC no 2 s-CEA, s-IL1a, s-IL1b, 3.92(1.08) 0.84 (0.8) 1.08 (1.08) 5.16 (0.8) 0.82 (0.12) s-MMPNG, s-sTNFR ACno 3 s-CEA, s-IL1a, s-MMPNG, 4 (0.96) 1.08 (0.81) 1 (0.96) 4.92 (0.81)0.81 (0.11) s-TM, s-TNFa OCR yes 1 s-IL2, s-IL10, s-NGAL, 3.16 (0.85)0.4 (0.5) 0.84 (0.85) 2.6 (0.5) 0.83 (0.13) s-NSE, s-VEGF OCR yes 2s-CEA, s-IL4, s-IL8, 3.24 (0.83) 0.56 (0.71) 0.76 (0.83) 2.44 (0.71)0.81 (0.17) s-NGAL, s-TM OCR yes 3 s-CEA, s-CRP, s-NGAL, 3.28 (0.84) 0.6(0.65) 0.72 (0.84) 2.4 (0.65) 0.81 (0.13) s-NSE, s-sTNFR alcohol 1s-CEA, s-IL1a, s-IL8, 3.36 (0.76) 0.56 (0.65) 0.64 (0.76) 2.44 (0.65)0.83 (0.12) no s-TM, s-sTNFR alcohol 2 s-CEA, s-IL1a, s-IL6, 3.28 (0.74)0.52 (0.65) 0.72 (0.74) 2.48 (0.65) 0.82 (0.13) no s-NGAL, s-TM alcohol3 s-CEA, s-IL1a, s-IL2, 3.24 (0.72) 0.52 (0.65) 0.76 (0.72) 2.48 (0.65)0.82 (0.15) no s-TM, s-sTNFR protein 1 s-CEA, s-IL8, s-IL10, 4.36 (0.7)0.44 (0.51) 0.64 (0.7) 1.56 (0.51) 0.83 (0.12) yes s-NSE, s-TNFa protein2 s-CEA, s-IL2, s-IL8, 4.4 (0.65) 0.52 (0.51) 0.6 (0.65) 1.48 (0.51)0.81 (0.14) yes s-MMPNG, s-NSE protein 3 s-CEA, s-IL2, s-IL6, 4.4 (0.65)0.6 (0.58) 0.6 (0.65) 1.4 (0.58) 0.79 (0.17) yes s-IL10, s-NSE alcohol 1s-CRP, s-IL1b, s-IL6, 3.12 (0.67) 0.72 (0.84) 0.88 (0.67) 4.28 (0.84)0.82 (0.13) yes s-IL8, s-NGAL alcohol 2 s-dDimer, s-IL1b, s-IL4, 2.8(0.76) 0.36 (0.57) 1.2 (0.76) 4.64 (0.57) 0.81 (0.1) yes s-Ifngg, s-NGALalcohol 3 s-CRP, s-IL1b, s-IL4, 3.12 (0.73) 0.76 (0.66) 0.88 (0.73) 4.24(0.66) 0.81 (0.13) yes s-MCP1, s-NGAL CI no 1 s-CEA, s-EGF, s-CRP, 1.4(0.65) 0.28 (0.46) 0.6 (0.65) 3.72 (0.46) 0.82 (0.17) s-IL4, s-Ifngg CIno 2 s-dDimer, s-FPSA, s-IL6, 1.32 (0.75) 0.12 (0.33) 0.68 (0.75) 3.88(0.33) 0.82 (0.18) s-Ifngg, s-NGAL CI no 3 s-IL1a, s-IL4, s-MMPNG, 1.48(0.59) 0.52 (0.82) 0.52 (0.59) 3.48 (0.82) 0.8 (0.19) s-NGAL, s-TM OCRno 1 s-CEA, s-dDimer, s-NSE, 3.08 (0.7) 0.56 (0.82) 0.92 (0.7) 3.44(0.82) 0.82 (0.13) s-TM, s-TPSA OCR no 2 s-CEA, s-EGF, s-IL10, 2.92(0.86) 0.4 (0.58) 1.08 (0.86) 3.6 (0.58) 0.82 (0.15) s-MCP1, s-sTNFR OCRno 3 s-CEA, s-dDimer, s-CRP, 2.96 (0.93) 0.48 (0.65) 1.04 (0.93) 3.52(0.65) 0.81 (0.14) s-MCP1, s-NGAL AC yes 1 s-IL6, s-IL8, s-NGAL, 2.52(0.59) 0.48 (0.51) 0.48 (0.59) 1.52 (0.51) 0.8 (0.15) s-TPSA, s-VEGF ACyes 2 s-FPSA, s-NGAL, s-TM, 2.52 (0.71) 0.52 (0.71) 0.48 (0.71) 1.48(0.71) 0.79 (0.22) s-TNFa, s-VEGF AC yes 3 s-IL1b, s-IL2, s-NGAL, 2.48(0.77) 0.56 (0.71) 0.52 (0.77) 1.44 (0.71) 0.77 (0.23) s-TM, s-VEGFage > 65 1 s-CEA, s-dDimer, s-IL4, 4.56 (0.58) 1.04 (0.68) 0.44 (0.58)1.96 (0.68) 0.78 (0.13) s-NGAL, s-TM age > 65 2 s-IL1a, s-MMPNG, s-NGAL,4.04 (0.84) 0.76 (0.6) 0.96 (0.84) 2.24 (0.6) 0.78 (0.13) s-sTNFR,s-TNFa age > 65 3 s-IL2, s-MMPNG, s-NGAL, 4.12 (0.93) 0.88 (0.6) 0.88(0.93) 2.12 (0.6) 0.77 (0.14) s-sTNFR, s-VEGF AH no 1 s-CEA, s-dDimer,s-IL4, 1.96 (0.73) 0.44 (0.65) 1.04 (0.73) 4.56 (0.65) 0.78 (0.11)s-MMPNG, s-sTNFR AH no 2 s-CEA, s-EGF, s-IL10, 1.76 (0.88) 0.24 (0.44)1.24 (0.88) 4.76 (0.44) 0.77 (0.14) s-MMPNG, s-TNFa AH no 3 s-CEA,s-dDimer, s-CRP, 1.8 (1) 0.4 (0.5) 1.2 (1) 4.6 (0.5) 0.76 (0.18) s-IL4,s-IL10 protein 1 s-FPSA, s-IL1a, s-IL4, 1.84 (0.75) 0.44 (0.65) 1.16(0.75) 4.56 (0.65) 0.76 (0.14) no s-Ifngg, s-NGAL protein 2 s-dDimer,s-IL2, s-IL4, 1.72 (0.79) 0.28 (0.46) 1.28 (0.79) 4.72 (0.46) 0.76(0.13) no s-NGAL, s-TM protein 3 s-dDimer, s-IL6, s-NGAL, 1.72 (0.74)0.28 (0.61) 1.28 (0.74) 4.72 (0.61) 0.76 (0.15) no s-TM, s-sTNFR AH yes1 s-CEA, s-NGAL, s-NSE, 4.52 (0.77) 0.88 (0.73) 0.48 (0.77) 1.12 (0.73)0.73 (0.19) s-TNFa, s-TPSA AH yes 2 s-CEA, s-MMPNG, s-NGAL, 4.56 (0.58)0.92 (0.7) 0.44 (0.58) 1.08 (0.7) 0.73 (0.17) s-TM, s-TNFa AH yes 3s-CEA, s-IL1b, s-NGAL, 4.64 (0.7) 0.96 (0.61) 0.36 (0.7) 1.04 (0.61)0.72 (0.18) s-sTNFR, s-TPSA CI yes 1 s-CEA, s-IL1a, s-NGAL, 4.6 (0.65)1.4 (0.71) 0.4 (0.65) 1.6 (0.71) 0.73 (0.14) s-NSE, s-TPSA CI yes 2s-IL1a, s-MMPNG, s-NGAL, 4.72 (0.68) 1.48 (0.96) 0.28 (0.68) 1.52 (0.96)0.73 (0.17) s-TPSA, s-VEGF CI yes 3 s-CEA, s-IL1a, s-IL10, 4.56 (0.65)1.48 (0.71) 0.44 (0.65) 1.52 (0.71) 0.71 (0.14) s-NGAL, s-VEGF smoking 1s-dDimer, s-EGF, s-IL1a, 5.04 (1.02) 1.76 (1.05) 0.96 (1.02) 2.24 (1.05)0.7 (0.17) yes s-IL8, s-NGAL smoking 2 s-IL1a, s-IL2, s-IL8, 4.8 (1.08)1.64 (0.99) 1.2 (1.08) 2.36 (0.99) 0.7 (0.13) yes s-NGAL, s-sTNFRsmoking 3 s-IL1a, s-IL10, s-NGAL, 4.92 (1) 1.72 (0.79) 1.08 (1) 2.28(0.79) 0.7 (0.13) yes s-NSE, s-TNFa

TABLE 6 Plasma 5 biomarker classifiers name num Biomarker TP FP FN TNAUC OCR no 1 p-IL4, p-IL6, p-Ifng, 3.64 (0.49) 1.2 (0.91) 0.36 (0.49)2.8 (0.91) 0.8 (0.11) p-MMPNG, p-NGAL OCR no 2 p-IL1b, p-IL4, p-IL10,3.64 (0.57) 1.28 (0.94) 0.36 (0.57) 2.72 (0.94) 0.8 (0.11) p-MMPNG, p-TMOCR no 3 p-IL2, p-IL4, p-IL6, 3.6 (0.65) 1.28 (0.89) 0.4 (0.65) 2.72(0.89) 0.79 (0.11) p-Ifng, p-MMPNG OCR yes 1 p-IL1a, p-IL6, p-MMPNG,3.28 (0.61) 0.88 (0.78) 0.72 (0.61) 2.12 (0.78) 0.76 (0.17) p-TM,p-sTNFR OCR yes 2 p-IL1a, p-IL1b, p-IL6, 2.84 (0.85) 0.6 (0.5) 1.16(0.85) 2.4 (0.5) 0.76 (0.14) p-IL8, p-TNFa OCR yes 3 p-IL8, p-MMPNG,p-NGAL, 2.68 (0.9) 0.48 (0.65) 1.32 (0.9) 2.52 (0.65) 0.76 (0.17) p-NSE,p-TNFa AC yes 1 p-IL2, p-Ifng, p-MCP1, 2.56 (0.65) 0.72 (0.68) 0.44(0.65) 1.28 (0.68) 0.75 (0.19) p-MMPNG, p-TM AC yes 2 p-IL1a, p-IL1b,p-IL6, 3 (0) 1.24 (0.6) 0 (0) 0.76 (0.6) 0.69 (0.15) p-TNFa, p-VEGF ACyes 3 p-IL4, p-IL6, p-Ifng, 2.4 (0.5) 0.88 (0.73) 0.6 (0.5) 1.12 (0.73)0.68 (0.19) p-MCP1, p-TNFa CI no 1 p-dDimer, p-IL1b, p-IL8, 1.32 (0.69)0.72 (0.94) 0.68 (0.69) 3.28 (0.94) 0.74 (0.2) p-MMPNG, p-TM CI no 2p-dDimer, p-IL8, p-TM, 1.16 (0.75) 0.4 (0.65) 0.84 (0.75) 3.6 (0.65)0.74 (0.2) p-TNFa, p-VEGF CI no 3 p-IL2, p-IL8, p-MMPNG, 1.24 (0.66)0.64 (0.64) 0.76 (0.66) 3.36 (0.64) 0.73 (0.18) p-TM, p-TNFa smoking 1p-IL1a, p-MMPNG, p-NSE, 1.2 (0.71) 0.36 (0.64) 0.8 (0.71) 2.64 (0.64)0.74 (0.18) no p-sTNFR, p-VEGF smoking 2 p-Ifng, p-MCP1, p-MMPNG, 1.2(0.71) 0.44 (0.71) 0.8 (0.71) 2.56 (0.71) 0.73 (0.21) no p-NGAL, p-NSEsmoking 3 p-Ifng, p-MMPNG, p-NGAL, 1.2 (0.76) 0.44 (0.51) 0.8 (0.76)2.56 (0.51) 0.73 (0.21) no p-NSE, p-TNFa age < 65 1 p-dDimer, p-IL8,p-IL10, 1.72 (0.94) 0.56 (0.71) 1.28 (0.94) 4.44 (0.71) 0.73 (0.17)p-NSE, p-VEGF age < 65 2 p-dDimer, p-IL8, p-MMPNG, 1.56 (1.08) 0.36(0.76) 1.44 (1.08) 4.64 (0.76) 0.72 (0.18) p-TNFa, p-VEGF age < 65 3p-EGF, p-IL8, p-IL10, 1.56 (0.87) 0.36 (0.57) 1.44 (0.87) 4.64 (0.57)0.72 (0.16) p-MMPNG, p-sTNFR protein 1 p-dDimer, p-IL4, p-MCP1, 1.6(0.96) 0.6 (0.87) 1.4 (0.96) 4.4 (0.87) 0.71 (0.19) no p-MMPNG, p-TNFaprotein 2 p-EGF, p-IL1a, p-IL2, 1.6 (0.76) 0.8 (0.76) 1.4 (0.76) 4.2(0.76) 0.69 (0.15) no p-MMPNG, p-NGAL protein 3 p-dDimer, p-IL4, p-MCP1,1.52 (0.96) 0.68 (0.75) 1.48 (0.96) 4.32 (0.75) 0.69 (0.19) no p-MMPNG,p-sTNFR AC no 1 p-IL1a, p-IL8, p-MMPNG, 2.96 (0.93) 1.12 (1.05) 2.04(0.93) 4.88 (1.05) 0.7 (0.14) p-NGAL, p-sTNFR AC no 2 p-IL1a, p-IL1b,p-IL4, 3 (0.76) 1.2 (0.96) 2 (0.76) 4.8 (0.96) 0.7 (0.11) p-Ifng,p-sTNFR AC no 3 p-IL1a, p-IL1b, p-IL8, 2.36 (1.15) 0.44 (0.65) 2.64(1.15) 5.56 (0.65) 0.7 (0.12) p-TM, p-sTNFR alcohol 1 p-IL1a, p-Ifng,p-MMPNG, 3.48 (0.82) 1.4 (0.96) 0.52 (0.82) 1.6 (0.96) 0.7 (0.21) nop-sTNFR, p-TNFa alcohol 2 p-EGF, p-IL4, p-MCP1, 3.48 (0.59) 1.44 (0.92)0.52 (0.59) 1.56 (0.92) 0.7 (0.16) no p-MMPNG, p-sTNFR alcohol 3 p-IL1a,p-IL8, p-IL10, 3.8 (0.41) 1.68 (0.8) 0.2 (0.41) 1.32 (0.8) 0.7 (0.15) nop-MMPNG, p-VEGF age > 65 1 p-CRP, p-IL1a, p-MMPNG, 4.8 (0.41) 1.68(0.85) 0.2 (0.41) 1.32 (0.85) 0.7 (0.16) p-TM, p-VEGF age > 65 2 p-CRP,p-IL1a, p-IL1b, 4.76 (0.52) 1.76 (0.93) 0.24 (0.52) 1.24 (0.93) 0.68(0.16) p-MMPNG, p-NGAL age > 65 3 p-CRP, p-IL1a, p-IL4, 4.76 (0.44) 1.8(0.65) 0.24 (0.44) 1.2 (0.65) 0.68 (0.1) p-MMPNG, p-TM alcohol 1p-dDimer, p-IL4, p-MMPNG, 2.84 (1.07) 1.64 (1.04) 1.16 (1.07) 3.36(1.04) 0.69 (0.14) yes p-NSE, p-TM alcohol 2 p-IL1b, p-IL4, p-MMPNG,2.96 (0.89) 1.92 (1) 1.04 (0.89) 3.08 (1) 0.68 (0.13) yes p-NSE, p-TNFaalcohol 3 p-EGF, p-CRP, p-IL4, 2.96 (0.93) 1.96 (1.17) 1.04 (0.93) 3.04(1.17) 0.67 (0.15) yes p-MMPNG, p-sTNFR AH no 1 p-EGF, p-IL1a, p-IL8,1.68 (0.95) 0.92 (0.7) 1.32 (0.95) 4.08 (0.7) 0.69 (0.15) p-MMPNG,p-VEGF AH no 2 p-IL1a, p-IL8, p-Ifng, 1.36 (0.99) 0.48 (0.71) 1.64(0.99) 4.52 (0.71) 0.68 (0.19) p-MMPNG, p-VEGF AH no 3 p-CRP, p-IL1a,p-IL8, 1.48 (0.65) 0.8 (0.71) 1.52 (0.65) 4.2 (0.71) 0.67 (0.16)p-MMPNG, p-NGAL smoking 1 p-IL4, p-Ifng, p-MCP1, 5.6 (0.65) 2.4 (0.71)0.4 (0.65) 1.6 (0.71) 0.67 (0.09) yes p-MMPNG, p-TM smoking 2 p-IL1a,p-IL4, p-Ifng, 5.48 (0.77) 2.36 (0.95) 0.52 (0.77) 1.64 (0.95) 0.66(0.13) yes p-MCP1, p-MMPNG smoking 3 p-EGF, p-IL1a, p-IL4, 5.64 (0.57)2.48 (1.05) 0.36 (0.57) 1.52 (1.05) 0.66 (0.12) yes p-MCP1, p-MMPNGprotein 1 p-CRP, p-IL1a, p-IL8, 4.56 (0.65) 1.16 (0.47) 0.44 (0.65) 0.84(0.47) 0.67 (0.13) yes p-Ifng, p-TM protein 2 p-CRP, p-IL1a, p-IL8, 4.72(0.61) 1.24 (0.6) 0.28 (0.61) 0.76 (0.6) 0.66 (0.17) yes p-Ifng, p-NGALprotein 3 p-IL1a, p-IL2, p-IL8, 4.8 (0.41) 1.28 (0.61) 0.2 (0.41) 0.72(0.61) 0.66 (0.16) yes p-MCP1, p-TM AH yes 1 p-IL1a, p-IL1b, p-IL4, 4.96(0.2) 1.52 (0.51) 0.04 (0.2) 0.48 (0.51) 0.62 (0.12) p-Ifng, p-VEGF AHyes 2 p-EGF, p-CRP, p-IL2, 4.8 (0.41) 1.48 (0.51) 0.2 (0.41) 0.52 (0.51)0.61 (0.13) p-IL4, p-IL8 AH yes 3 p-EGF, p-CRP, p-IL2, 5 (0) 1.56 (0.51)0 (0) 0.44 (0.51) 0.61 (0.13) p-IL10, p-NGAL CI yes 1 p-IL1a, p-IL6,p-IL8, 4.48 (0.51) 2.12 (0.78) 0.52 (0.51) 0.88 (0.78) 0.59 (0.15)p-MMPNG, p-NSE CI yes 2 p-IL6, p-Ifng, p-MMPNG, 4.52 (0.65) 2.2 (0.71)0.48 (0.65) 0.8 (0.71) 0.59 (0.11) p-NSE, p-sTNFR CI yes 3 p-IL1a,p-IL1b, p-IL8, 4.96 (0.2) 2.52 (0.51) 0.04 (0.2) 0.48 (0.51) 0.58 (0.08)p-IL10, p-MMPNG

TABLE 7 Urine 6 biomarker classifiers name num Biomarker TP FP FN TN AUCsmoking 1 u-BTA, u-MCP1, u-MMP9, 1.72 (0.46) 0.16 (0.37) 0.28 (0.46)2.84 (0.37) 0.9 (0.15) no u-sTNFR2, u-vWF, u-FAS smoking 2 u-dDimer,u-IL6, u-IL8, 1.64 (0.57) 0.08 (0.28) 0.36 (0.57) 2.92 (0.28) 0.9 (0.15)no u-NGAL, u-NSE, u-TNFa smoking 3 u-BTA, u-IL6, u-MCP1, 1.68 (0.56)0.16 (0.37) 0.32 (0.56) 2.84 (0.37) 0.89 (0.15) no u-TNFa, u-sTNFR2,u-FAS age < 65 1 u-EGF, u-IL2, u-IL8, 2.48 (0.71) 0.32 (0.63) 0.52(0.71) 4.68 (0.63) 0.88 (0.13) u-MMP9, u-HA, u-CK18 age < 65 2 u-BTA,u-EGF, u-IL1b, 2.36 (0.64) 0.36 (0.64) 0.64 (0.64) 4.64 (0.64) 0.86(0.13) u-IL8, u-HA, u-CK18 age < 65 3 u-dDimer, u-EGF, u-NSE, 2.36 (0.7)0.36 (0.49) 0.64 (0.7) 4.64 (0.49) 0.86 (0.13) u-vWF, u-HA, u-CK18 OCRyes 1 u-BTA, u-dDimer, u-CRP, 3.6 (0.65) 0.44 (0.58) 0.4 (0.65) 2.56(0.58) 0.88 (0.14) u-IL4, u-sTNFR, u-vWF OCR yes 2 u-IL4, u-IL8, u-NGAL,3.2 (0.82) 0.2 (0.5) 0.8 (0.82) 2.8 (0.5) 0.87 (0.12) u-NSE, u-TM,u-sTNFR OCR yes 3 u-CRP, u-IL2, u-IL8, 3.4 (0.82) 0.36 (0.57) 0.6 (0.82)2.64 (0.57) 0.86 (0.16) u-MCP1, u-MMP9NG, u-TNFa CI no 1 u-dDimer,u-EGF, u-CRP, 1.8 (0.41) 0.64 (0.81) 0.2 (0.41) 3.36 (0.81) 0.87 (0.12)u-IL4, u-sTNFR, u-vWF CI no 2 u-dDimer, u-EGF, u-CRP, 1.56 (0.51) 0.2(0.5) 0.44 (0.51) 3.8 (0.5) 0.86 (0.14) u-IL4, u-sTNFR, u-sTNFR2 CI no 3u-EGF, u-IL2, u-IL4, 1.6 (0.65) 0.32 (0.48) 0.4 (0.65) 3.68 (0.48) 0.86(0.19) u-sTNFR2, u-VEGF, u-vWF AC no 1 u-EGF, u-CRP, u-IL4, 3.92 (0.7)0.44 (0.77) 1.08 (0.7) 5.56 (0.77) 0.86 (0.08) u-VEGF, u-HA, u-CK18 ACno 2 u-EGF, u-IL4, u-IL6, 3.88 (0.83) 0.48 (0.77) 1.12 (0.83) 5.52(0.77) 0.85 (0.12) u-IL8, u-vWF, u-CK18 AC no 3 u-BTA, u-EGF, u-IL4, 3.8(0.91) 0.48 (0.51) 1.2 (0.91) 5.52 (0.51) 0.84 (0.09) u-IL8, u-HA,u-CK18 AC yes 1 u-dDimer, u-IL6, u-NGAL, 2.4 (0.71) 0.24 (0.6) 0.6(0.71) 1.76 (0.6) 0.84 (0.2) u-NSE, u-VEGF, u-HA AC yes 2 u-IL1b, u-IL6,u-IL8, 2.44 (0.58) 0.28 (0.46) 0.56 (0.58) 1.72 (0.46) 0.84 (0.14)u-MMP9NG, u-NSE, u-VEGF AC yes 3 u-BTA, u-dDimer, u-IL6, 2.36 (0.64)0.24 (0.52) 0.64 (0.64) 1.76 (0.52) 0.83 (0.19) u-NGAL, u-NSE, u-VEGFalcohol 1 u-dDimer, u-EGF, u-CRP, 3.48 (0.71) 0.96 (0.89) 0.52 (0.71)4.04 (0.89) 0.84 (0.12) yes u-IL1a, u-IL6, u-vWF alcohol 2 u-EGF, u-CRP,u-IL1a, 3.56 (0.65) 1.08 (0.95) 0.44 (0.65) 3.92 (0.95) 0.84 (0.11) yesu-sTNFR, u-vWF, u-CK18 alcohol 3 u-BTA, u-EGF, u-CRP, 3.6 (0.65) 1.16(1.11) 0.4 (0.65) 3.84 (1.11) 0.83 (0.13) yes u-IL1a, u-vWF, u-FAS age >65 1 u-BTA, u-IL1b, u-IL4, 4.72 (0.46) 0.8 (0.82) 0.28 (0.46) 2.2 (0.82)0.84 (0.15) u-VEGF, u-vWF, u-HA age > 65 2 u-BTA, u-IL1b, u-IL8, 4.64(0.49) 0.96 (0.84) 0.36 (0.49) 2.04 (0.84) 0.8 (0.16) u-sTNFR2, u-vWF,u-HA age > 65 3 u-BTA, u-EGF, u-IL1a, 4.68 (0.48) 1 (0.65) 0.32 (0.48) 2(0.65) 0.8 (0.12) u-NSE, u-vWF, u-HA alcohol 1 u-IL2, u-IL4, u-IL8, 3.28(0.74) 0.48 (0.65) 0.72 (0.74) 2.52 (0.65) 0.83 (0.14) no u-NGAL, u-HA,u-CK18 alcohol 2 u-BTA, u-dDimer, u-IL2, 3.12 (0.78) 0.4 (0.65) 0.88(0.78) 2.6 (0.65) 0.82 (0.11) no u-IL8, u-MMP9NG, u-CK18 alcohol 3u-IL2, u-IL4, u-IL8, 3.28 (0.84) 0.6 (0.71) 0.72 (0.84) 2.4 (0.71) 0.81(0.15) no u-sTNFR2, u-HA, u-CK18 protein 1 u-EGF, u-IL8, u-sTNFR2, 4.4(0.65) 0.48 (0.51) 0.6 (0.65) 1.52 (0.51) 0.82 (0.12) yes u-VEGF, u-vWF,u-HA protein 2 u-EGF, u-IL1a, u-MMP9, 4.36 (0.91) 0.48 (0.71) 0.64(0.91) 1.52 (0.71) 0.82 (0.19) yes u-NSE, u-vWF, u-HA protein 3 u-EGF,u-CRP, u-IL2, 4.8 (0.41) 0.68 (0.63) 0.2 (0.41) 1.32 (0.63) 0.81 (0.17)yes u-IL4, u-TM, u-CK18 protein 1 u-CRP, u-MCP1, u-MMP9, 2.2 (0.65) 0.52(0.65) 0.8 (0.65) 4.48 (0.65) 0.81 (0.12) no u-NGAL, u-sTNFR2, u-VEGFprotein 2 u-dDimer, u-CRP, u-IL2, 2.2 (0.91) 0.68 (0.85) 0.8 (0.91) 4.32(0.85) 0.8 (0.14) no u-IL4, u-NGAL, u-sTNFR protein 3 u-BTA, u-CRP,u-IL2, 2.24 (0.66) 0.76 (0.88) 0.76 (0.66) 4.24 (0.88) 0.8 (0.13) nou-NGAL, u-sTNFR2, u-vWF smoking 1 u-dDimer, u-EGF, u-IL1b, 5.8 (0.41)1.36 (0.95) 0.2 (0.41) 2.64 (0.95) 0.81 (0.12) yes u-IL8, u-VEGF, u-vWFsmoking 2 u-EGF, u-IL1b, u-NSE, 5.56 (0.58) 1.24 (0.83) 0.44 (0.58) 2.76(0.83) 0.81 (0.13) yes u-sTNFR2, u-VEGF, u-vWF smoking 3 u-EGF, u-IL2,u-TM, 5.4 (0.87) 1.24 (0.83) 0.6 (0.87) 2.76 (0.83) 0.8 (0.12) yesu-sTNFR2, u-VEGF, u-CK18 AH no 1 u-EGF, u-NGAL, u-VEGF, 2.16 (0.75) 0.52(0.71) 0.84 (0.75) 4.48 (0.71) 0.81 (0.14) u-vWF, u-HA, u-CK18 AH no 2u-CRP, u-IL1b, u-IL6, 1.88 (0.73) 0.08 (0.28) 1.12 (0.73) 4.92 (0.28)0.81 (0.12) u-sTNFR, u-VEGF, u-vWF AH no 3 u-dDimer, u-EGF, u-IL4, 2.04(0.79) 0.36 (0.76) 0.96 (0.79) 4.64 (0.76) 0.8 (0.13) u-VEGF, u-HA,u-CK18 AH yes 1 u-BTA, u-EGF, u-IL1b, 4.88 (0.44) 0.76 (0.66) 0.12(0.44) 1.24 (0.66) 0.8 (0.18) u-IL8, u-VEGF, u-vWF AH yes 2 u-dDimer,u-CRP, u-IL8, 4.68 (0.48) 0.68 (0.69) 0.32 (0.48) 1.32 (0.69) 0.8 (0.16)u-sTNFR2, u-vWF, u-CK18 AH yes 3 u-dDimer, u-EGF, u-IL2, 4.88 (0.33) 0.8(0.65) 0.12 (0.33) 1.2 (0.65) 0.79 (0.16) u-VEGF, u-vWF, u-FAS OCR no 1u-IL6, u-MCP1, u-TNFa, 3.08 (0.64) 0.76 (0.78) 0.92 (0.64) 3.24 (0.78)0.79 (0.12) u-vWF, u-FAS, u-CK18 OCR no 2 u-BTA, u-dDimer, u-CRP, 2.76(1.01) 0.52 (0.71) 1.24 (1.01) 3.48 (0.71) 0.78 (0.15) u-TNFa, u-vWF,u-HA OCR no 3 u-BTA, u-IL1a, u-TNFa, 2.8 (0.71) 0.56 (0.71) 1.2 (0.71)3.44 (0.71) 0.78 (0.14) u-vWF, u-HA, u-FAS CI yes 1 u-BTA, u-IL2,u-MMP9NG, 4.48 (0.59) 1.04 (0.93) 0.52 (0.59) 1.96 (0.93) 0.77 (0.16)u-sTNFR, u-TNFa, u-VEGF CI yes 2 u-BTA, u-IL2, u-MMP9NG, 4.72 (0.46) 1.2(0.58) 0.28 (0.46) 1.8 (0.58) 0.77 (0.1) u-NGAL, u-TNFa, u-CK18 CI yes 3u-BTA, u-IL2, u-MMP9NG, 4.32 (0.75) 1 (0.91) 0.68 (0.75) 2 (0.91) 0.77(0.18) u-NSE, u-VEGF, u-CK18

TABLE 8 Serum 6 biomarker classifiers name num Biomarker TP FP FN TN AUCsmoking 1 s-CEA, s-IL6, s-IL8, 1.84 (0.37) 0.04 (0.2) 0.16 (0.37) 2.96(0.2) 0.95 (0.1) no s-MMPNG, s-NGAL, s-VEGF smoking 2 s-CEA, s-dDimer,s-CRP, 1.8 (0.41) 0.08 (0.28) 0.2 (0.41) 2.92 (0.28) 0.94 (0.11) nos-MMPNG, s-NGAL, s-NSE smoking 3 s-CEA, s-CRP, s-IL2, 1.8 (0.41) 0.12(0.33) 0.2 (0.41) 2.88 (0.33) 0.93 (0.12) no s-MMPNG, s-NGAL, s-TMprotein 1 s-CEA, s-IL1b, s-IL2, 4.44 (0.87) 0.36 (0.57) 0.56 (0.87) 1.64(0.57) 0.85 (0.18) yes s-IL8, s-IL10, s-NSE protein 2 s-CEA, s-IL1b,s-IL2, 4.8 (0.5) 0.64 (0.57) 0.2 (0.5) 1.36 (0.57) 0.82 (0.15) yess-IL8, s-NSE, s-TPSA protein 3 s-CEA, s-CRP, s-IL10, 4.64 (0.49) 0.6(0.65) 0.36 (0.49) 1.4 (0.65) 0.81 (0.15) yes s-MMPNG, s-NGAL, s-VEGFage < 65 1 s-CEA, s-IL1a, s-IL4, 2.4 (0.58) 0.56 (0.82) 0.6 (0.58) 4.44(0.82) 0.84 (0.11) s-IL8, s-MMPNG, s-sTNFR age < 65 2 s-CEA, s-IL1a,s-IL2, 2.32 (0.85) 0.6 (0.71) 0.68 (0.85) 4.4 (0.71) 0.83 (0.16) s-IL4,s-NSE, s-sTNFR age < 65 3 s-CEA, s-EGF, s-IL1a, 2.24 (0.83) 0.48 (0.51)0.76 (0.83) 4.52 (0.51) 0.83 (0.16) s-IL4, s-IL8, s-TM alcohol 1 s-CEA,s-IL2, s-IL8, 3.52 (0.65) 0.6 (0.65) 0.48 (0.65) 2.4 (0.65) 0.84 (0.14)no s-NSE, s-TM, s-sTNFR alcohol 2 s-CEA, s-IL10, s-MMPNG, 3.32 (0.69)0.52 (0.65) 0.68 (0.69) 2.48 (0.65) 0.83 (0.15) no s-NSE, s-TM, s-sTNFRalcohol 3 s-CEA, s-CRP, s-IL2, 3.36 (0.76) 0.56 (0.58) 0.64 (0.76) 2.44(0.58) 0.83 (0.13) no s-IL10, s-NGAL, s-TM OCR no 1 s-CEA, s-dDimer,s-EGF, 3.04 (0.84) 0.36 (0.57) 0.96 (0.84) 3.64 (0.57) 0.84 (0.12)s-IL8, s-IL10, s-TM OCR no 2 s-CEA, s-dDimer, s-IL4, 3.24 (0.88) 0.56(0.65) 0.76 (0.88) 3.44 (0.65) 0.84 (0.14) s-MCP1, s-MMPNG, s-sTNFR OCRno 3 s-CEA, s-dDimer, s-EGF, 3.04 (0.79) 0.4 (0.58) 0.96 (0.79) 3.6(0.58) 0.83 (0.12) s-IL6, s-NGAL, s-TM OCR yes 1 s-dDimer, s-CRP, s-IL6,3.24 (0.83) 0.44 (0.58) 0.76 (0.83) 2.56 (0.58) 0.83 (0.13) s-IL8,s-NSE, s-sTNFR OCR yes 2 s-CEA, s-IL4, s-IL10, 3.32 (0.56) 0.52 (0.77)0.68 (0.56) 2.48 (0.77) 0.83 (0.12) s-Ifngg, s-MCP1, s-NGAL OCR yes 3s-FPSA, s-IL4, s-IL8, 3.28 (1.02) 0.52 (0.77) 0.72 (1.02) 2.48 (0.77)0.82 (0.14) s-MMPNG, s-NSE, s-sTNFR CI no 1 s-IL4, s-MMPNG, s-NGAL, 1.52(0.65) 0.4 (0.5) 0.48 (0.65) 3.6 (0.5) 0.83 (0.2) s-NSE, s-sTNFR, s-TPSACI no 2 s-CEA, s-EGF, s-FPSA, 1.68 (0.48) 0.76 (0.78) 0.32 (0.48) 3.24(0.78) 0.82 (0.16) s-IL4, s-NSE, s-sTNFR CI no 3 s-CEA, s-EGF, s-FPSA,1.44 (0.71) 0.32 (0.56) 0.56 (0.71) 3.68 (0.56) 0.82 (0.2) s-IL4,s-MCP1, s-VEGF AC no 1 s-CEA, s-IL1a, s-IL1b, 3.76 (1.01) 0.6 (0.71)1.24 (1.01) 5.4 (0.71) 0.83 (0.12) s-IL6, s-NGAL, s-NSE AC no 2 s-CEA,s-IL4, s-IL6, 3.96 (0.89) 0.84 (0.75) 1.04 (0.89) 5.16 (0.75) 0.83(0.11) s-IL8, s-MMPNG, s-TNFa AC no 3 s-CEA, s-dDimer, s-IL1a, 3.84(0.94) 0.72 (0.84) 1.16 (0.94) 5.28 (0.84) 0.82 (0.11) s-IL4, s-IL6,s-sTNFR AH no 1 s-CEA, s-dDimer, s-CRP, 2.16 (0.8) 0.36 (0.49) 0.84(0.8) 4.64 (0.49) 0.82 (0.12) s-IL4, s-IL10, s-TM AH no 2 s-CEA,s-dDimer, s-CRP, 2.08 (0.76) 0.36 (0.57) 0.92 (0.76) 4.64 (0.57) 0.81(0.14) s-IL4, s-IL6, s-MMPNG AH no 3 s-CEA, s-dDimer, s-IL2, 1.96 (0.98)0.44 (0.58) 1.04 (0.98) 4.56 (0.58) 0.78 (0.16) s-IL4, s-IL8, s-MMPNGalcohol 1 s-EGF, s-CRP, s-IL1a, 3.24 (0.72) 0.84 (0.94) 0.76 (0.72) 4.16(0.94) 0.82 (0.13) yes s-IL1b, s-NGAL, s-TPSA alcohol 2 s-CEA, s-CRP,s-IL1b, 2.88 (1.09) 0.4 (0.58) 1.12 (1.09) 4.6 (0.58) 0.82 (0.16) yess-IL2, s-NGAL, s-NSE alcohol 3 s-CEA, s-dDimer, s-CRP, 3.08 (0.86) 0.8(0.87) 0.92 (0.86) 4.2 (0.87) 0.8 (0.14) yes s-IL1a, s-IL6, s-NGAL ACyes 1 s-IL1a, s-MCP1, s-MMPNG, 2.8 (0.41) 0.64 (0.76) 0.2 (0.41) 1.36(0.76) 0.81 (0.18) s-NGAL, s-TM, s-TNFa AC yes 2 s-CEA, s-FPSA, s-IL8,2.48 (0.59) 0.52 (0.65) 0.52 (0.59) 1.48 (0.65) 0.78 (0.19) s-NGAL,s-TM, s-VEGF AC yes 3 s-FPSA, s-IL4, s-NGAL, 2.4 (0.65) 0.48 (0.59) 0.6(0.65) 1.52 (0.59) 0.78 (0.16) s-NSE, s-TNFa, s-VEGF age > 65 1 s-CEA,s-dDimer, s-IL1a, 4.08 (0.95) 0.68 (0.8) 0.92 (0.95) 2.32 (0.8) 0.79(0.15) s-NGAL, s-NSE, s-TM age > 65 2 s-CEA, s-EGF, s-IL1a, 4.32 (0.8)0.88 (0.83) 0.68 (0.8) 2.12 (0.83) 0.79 (0.15) s-MMPNG, s-NGAL, s-TPSAage > 65 3 s-CEA, s-dDimer, s-CRP, 4.36 (0.7) 0.96 (0.73) 0.64 (0.7)2.04 (0.73) 0.78 (0.13) s-IL1b, s-NGAL, s-TM protein 1 s-dDimer, s-IL1b,s-IL8, 1.88 (0.73) 0.24 (0.52) 1.12 (0.73) 4.76 (0.52) 0.79 (0.14) nos-NGAL, s-TM, s-TNFa protein 2 s-CEA, s-IL4, s-IL8, 1.96 (0.79) 0.52(0.59) 1.04 (0.79) 4.48 (0.59) 0.77 (0.15) no s-NGAL, s-TNFa, s-TPSAprotein 3 s-dDimer, s-FPSA, s-IL2, 1.8 (0.76) 0.32 (0.56) 1.2 (0.76)4.68 (0.56) 0.77 (0.13) no s-IL6, s-IL8, s-NGAL AH yes 1 s-CEA, s-IL1b,s-IL10, 4.32 (0.85) 0.64 (0.7) 0.68 (0.85) 1.36 (0.7) 0.77 (0.19)s-NGAL, s-TM, s-VEGF AH yes 2 s-CEA, s-dDimer, s-IL1b, 4.32 (0.8) 0.76(0.6) 0.68 (0.8) 1.24 (0.6) 0.74 (0.17) s-MMPNG, s-NGAL, s-TM AH yes 3s-CEA, s-EGF, s-IL1a, 4.64 (0.57) 0.92 (0.64) 0.36 (0.57) 1.08 (0.64)0.73 (0.16) s-IL1b, s-NGAL, s-TNFa CI yes 1 s-CEA, s-IL10, s-MMPNG, 4.64(0.57) 1.4 (0.91) 0.36 (0.57) 1.6 (0.91) 0.73 (0.17) s-NGAL, s-TNFa,s-VEGF CI yes 2 s-IL1a, s-IL10, s-MMPNG, 4.68 (0.63) 1.44 (0.92) 0.32(0.63) 1.56 (0.92) 0.73 (0.15) s-NGAL, s-NSE, s-VEGF CI yes 3 s-CRP,s-IL10, s-MMPNG, 4.76 (0.44) 1.52 (0.96) 0.24 (0.44) 1.48 (0.96) 0.72(0.17) s-NGAL, s-TPSA, s-VEGF smoking 1 s-dDimer, s-IL2, s-IL10, 5.24(0.93) 1.76 (1.01) 0.76 (0.93) 2.24 (1.01) 0.72 (0.16) yes s-MMPNG,s-NGAL, s-sTNFR smoking 2 s-EGF, s-FPSA, s-IL10, 5.12 (1.09) 1.76 (0.83)0.88 (1.09) 2.24 (0.83) 0.71 (0.16) yes s-NGAL, s-TNFa, s-TPSA smoking 3s-CEA, s-IL1a, s-IL4, 4.68 (0.75) 1.52 (0.77) 1.32 (0.75) 2.48 (0.77)0.7 (0.12) yes s-IL8, s-IL10, s-NGAL

TABLE 9 Plasma 6 biomarker classifiers name num Biomarker TP FP FN TNAUC OCR no 1 p-IL2, p-IL4, p-IL10, 3.52 (0.96) 1.12 (0.67) 0.48 (0.96)2.88 (0.67) 0.8 (0.13) p-MMPNG, p-TNFa, p-VEGF OCR no 2 p-CRP, p-IL4,p-IL10, 3.48 (0.71) 1.24 (0.97) 0.52 (0.71) 2.76 (0.97) 0.78 (0.14)p-MMPNG, p-TNFa, p-VEGF OCR no 3 p-IL1a, p-IL4, p-IL10, 3.48 (0.65) 1.28(0.68) 0.52 (0.65) 2.72 (0.68) 0.78 (0.11) p-Ifng, p-MMPNG, p-NSEsmoking 1 p-IL6, p-Ifng, p-MMPNG, 1.36 (0.64) 0.24 (0.52) 0.64 (0.64)2.76 (0.52) 0.8 (0.2) no p-NGAL, p-NSE, p-TNFa smoking 2 p-dDimer,p-IL1a, p-IL4, 1.36 (0.57) 0.36 (0.57) 0.64 (0.57) 2.64 (0.57) 0.78(0.18) no p-MMPNG, p-NSE, p-VEGF smoking 3 p-dDimer, p-EGF, p-IL1a, 1.24(0.78) 0.32 (0.48) 0.76 (0.78) 2.68 (0.48) 0.76 (0.23) no p-IL8,p-MMPNG, p-NSE OCR yes 1 p-IL1b, p-IL2, p-IL8, 3.04 (0.89) 0.64 (0.7)0.96 (0.89) 2.36 (0.7) 0.77 (0.16) p-MMPNG, p-NGAL, p-NSE OCR yes 2p-IL1b, p-IL8, p-IL10, 2.88 (1.01) 0.52 (0.77) 1.12 (1.01) 2.48 (0.77)0.77 (0.19) p-MCP1, p-NGAL, p-TM OCR yes 3 p-IL8, p-Ifng, p-MMPNG, 2.88(0.83) 0.52 (0.51) 1.12 (0.83) 2.48 (0.51) 0.77 (0.14) p-TM, p-sTNFR,p-TNFa CI no 1 p-dDimer, p-IL8, p-MMPNG, 1.28 (0.74) 0.44 (0.65) 0.72(0.74) 3.56 (0.65) 0.76 (0.21) p-NSE, p-TM, p-TNFa CI no 2 p-dDimer,p-IL2, p-IL8, 1.28 (0.68) 0.52 (0.65) 0.72 (0.68) 3.48 (0.65) 0.76(0.18) p-MMPNG, p-NSE, p-TNFa CI no 3 p-dDimer, p-IL8, p-Ifng, 1.2(0.71) 0.36 (0.49) 0.8 (0.71) 3.64 (0.49) 0.76 (0.2) p-MMPNG, p-sTNFR,p-TNFa alcohol 1 p-IL1a, p-IL1b, p-IL10, 3.92 (0.28) 1.48 (0.96) 0.08(0.28) 1.52 (0.96) 0.74 (0.17) no p-Ifng, p-MMPNG, p-VEGF alcohol 2p-EGF, p-CRP, p-IL1a, 3.8 (0.41) 1.56 (0.92) 0.2 (0.41) 1.44 (0.92) 0.72(0.17) no p-MMPNG, p-TNFa, p-VEGF alcohol 3 p-IL1a, p-IL6, p-IL8, 3.4(0.65) 1.28 (0.79) 0.6 (0.65) 1.72 (0.79) 0.71 (0.14) no p-Ifng,p-MMPNG, p-sTNFR AC no 1 p-dDimer, p-IL1a, p-IL4, 3.72 (1.1) 1.64 (1.04)1.28 (1.1) 4.36 (1.04) 0.74 (0.14) p-IL10, p-MMPNG, p-TNFa AC no 2p-CRP, p-IL8, p-IL10, 3.2 (1.22) 1.36 (1.22) 1.8 (1.22) 4.64 (1.22) 0.71(0.18) p-MMPNG, p-TM, p-sTNFR AC no 3 p-dDimer, p-IL1a, p-IL1b, 2.92(1.22) 1.04 (0.93) 2.08 (1.22) 4.96 (0.93) 0.71 (0.13) p-IL4, p-TM,p-sTNFR age < 65 1 p-EGF, p-CRP, p-IL6, 1.6 (0.71) 0.32 (0.75) 1.4(0.71) 4.68 (0.75) 0.73 (0.11) p-IL8, p-IL10, p-sTNFR age < 65 2 p-CRP,p-IL6, p-IL8, 1.64 (0.86) 0.4 (0.65) 1.36 (0.86) 4.6 (0.65) 0.73 (0.16)p-IL10, p-Ifng, p-sTNFR age < 65 3 p-dDimer, p-IL4, p-IL8, 1.72 (0.74)0.56 (0.77) 1.28 (0.74) 4.44 (0.77) 0.73 (0.14) p-MMPNG, p-NGAL, p-TNFaprotein 1 p-dDimer, p-IL1b, p-IL4, 1.8 (0.82) 0.76 (0.6) 1.2 (0.82) 4.24(0.6) 0.72 (0.16) no p-IL8, p-IL10, p-MMPNG protein 2 p-dDimer, p-EGF,p-IL8, 1.72 (0.74) 0.88 (1.27) 1.28 (0.74) 4.12 (1.27) 0.7 (0.16) nop-IL10, p-MMPNG, p-TM protein 3 p-dDimer, p-EGF, p-Ifng, 1.56 (0.92)0.64 (0.64) 1.44 (0.92) 4.36 (0.64) 0.7 (0.15) no p-MMPNG, p-NSE, p-VEGFAH no 1 p-EGF, p-CRP, p-IL1b, 1.84 (0.8) 0.84 (0.8) 1.16 (0.8) 4.16(0.8) 0.72 (0.13) p-IL8, p-MMPNG, p-VEGF AH no 2 p-CRP, p-IL1a, p-IL6,1.28 (0.89) 0.2 (0.41) 1.72 (0.89) 4.8 (0.41) 0.69 (0.16) p-IL8, p-IL10,p-MMPNG AH no 3 p-EGF, p-IL1b, p-IL4, 1.6 (0.87) 0.88 (1.01) 1.4 (0.87)4.12 (1.01) 0.68 (0.16) p-IL8, p-MMPNG, p-VEGF alcohol 1 p-IL1a, p-IL2,p-IL4, 2.76 (0.97) 1.36 (1.15) 1.24 (0.97) 3.64 (1.15) 0.71 (0.14) yesp-MMPNG, p-NSE, p-TNFa alcohol 2 p-IL2, p-IL4, p-IL6, 2.8 (0.76) 1.76(1.3) 1.2 (0.76) 3.24 (1.3) 0.67 (0.18) yes p-MMPNG, p-NSE, p-TM alcohol3 p-CRP, p-IL1a, p-IL1b, 2.72 (0.79) 1.68 (0.9) 1.28 (0.79) 3.32 (0.9)0.67 (0.12) yes p-IL4, p-MMPNG, p-TNFa age > 65 1 p-CRP, p-IL1a, p-IL2,4.8 (0.5) 1.64 (0.7) 0.2 (0.5) 1.36 (0.7) 0.71 (0.1) p-IL4, p-MMPNG,p-TM age > 65 2 p-EGF, p-CRP, p-IL1a, 4.92 (0.28) 1.76 (0.72) 0.08(0.28) 1.24 (0.72) 0.7 (0.13) p-IL1b, p-MMPNG, p-VEGF age > 65 3 p-EGF,p-IL1a, p-IL6, 4.8 (0.41) 1.72 (0.94) 0.2 (0.41) 1.28 (0.94) 0.69 (0.15)p-MMPNG, p-TM, p-TNFa AC yes 1 p-dDimer, p-IL2, p-IL6, 2.24 (0.52) 0.68(0.56) 0.76 (0.52) 1.32 (0.56) 0.7 (0.15) p-MMPNG, p-TM, p-TNFa AC yes 2p-IL2, p-IL10, p-Ifng, 2.36 (0.64) 0.76 (0.6) 0.64 (0.64) 1.24 (0.6) 0.7(0.16) p-MCP1, p-MMPNG, p-TNFa AC yes 3 p-IL6, p-MCP1, p-NGAL, 2.48(0.71) 0.84 (0.62) 0.52 (0.71) 1.16 (0.62) 0.7 (0.18) p-NSE, p-TM,p-TNFa smoking 1 p-dDimer, p-IL1a, p-IL4, 5.48 (0.71) 2.16 (0.99) 0.52(0.71) 1.84 (0.99) 0.69 (0.13) yes p-IL10, p-MMPNG, p-sTNFR smoking 2p-IL4, p-IL10, p-MMPNG, 5.48 (0.87) 2.16 (0.69) 0.52 (0.87) 1.84 (0.69)0.69 (0.1) yes p-TM, p-sTNFR, p-TNFa smoking 3 p-IL1b, p-IL4, p-IL8,5.52 (0.71) 2.32 (0.8) 0.48 (0.71) 1.68 (0.8) 0.67 (0.12) yes p-MCP1,p-MMPNG, p-TNFa protein 1 p-EGF, p-IL1a, p-IL4, 4.64 (0.57) 1.12 (0.78)0.36 (0.57) 0.88 (0.78) 0.68 (0.21) yes p-IL8, p-Ifng, p-TM protein 2p-dDimer, p-IL1a, p-IL8, 4.76 (0.44) 1.24 (0.72) 0.24 (0.44) 0.76 (0.72)0.67 (0.18) yes p-Ifng, p-MCP1, p-TM protein 3 p-IL1a, p-IL8, p-Ifng,4.56 (0.77) 1.16 (0.69) 0.44 (0.77) 0.84 (0.69) 0.67 (0.21) yes p-MCP1,p-TM, p-TNFa AH yes 1 p-EGF, p-IL6, p-IL10, 4.8 (0.41) 1.44 (0.65) 0.2(0.41) 0.56 (0.65) 0.62 (0.13) p-Ifng, p-MCP1, p-MMPNG AH yes 2p-dDimer, p-EGF, p-IL1b, 4.56 (0.58) 1.4 (0.58) 0.44 (0.58) 0.6 (0.58)0.61 (0.14) p-IL4, p-IL6, p-MCP1 AH yes 3 p-EGF, p-CRP, p-IL1b, 4.56(0.71) 1.4 (0.58) 0.44 (0.71) 0.6 (0.58) 0.61 (0.14) p-IL2, p-MMPNG,p-NGAL CI yes 1 p-IL6, p-IL8, p-Ifng, 4.48 (0.71) 2.12 (0.73) 0.52(0.71) 0.88 (0.73) 0.59 (0.12) p-MMPNG, p-NGAL, p-NSE CI yes 2 p-IL1a,p-IL6, p-MMPNG, 4.52 (0.59) 2.16 (0.62) 0.48 (0.59) 0.84 (0.62) 0.59(0.14) p-NSE, p-TM, p-TNFa CI yes 3 p-dDimer, p-IL4, p-IL8, 4.8 (0.41)2.36 (0.64) 0.2 (0.41) 0.64 (0.64) 0.59 (0.1) p-Ifng, p-MMPNG, p-VEGF

TABLE 10 Urine 7 biomarker classifiers name num Biomarker TP FP FN TNAUC smoking 1 u-EGF, u-CRP, u-IL8, u-NGAL, 1.84 (0.37) 0.24 (0.44) 0.16(0.37) 2.76 (0.44) 0.92 (0.1) no u-NSE, u-TM, u-HA smoking 2 u-BTA,u-EGF, u-IL8, u-MCP1, 1.68 (0.48) 0.16 (0.37) 0.32 (0.48) 2.84 (0.37)0.89 (0.14) no u-NGAL, u-NSE, u-sTNFR smoking 3 u-BTA, u-IL4, u-MCP1,u-TM, 1.6 (0.5) 0.04 (0.2) 0.4 (0.5) 2.96 (0.2) 0.89 (0.12) no u-sTNFR2,u-vWF, u-FAS OCR yes 1 u-EGF, u-IL1a, u-IL8, u-MMP9NG, 3.72 (0.46) 0.4(0.5) 0.28 (0.46) 2.6 (0.5) 0.9 (0.1) u-NSE, u-vWF, u-CK18 OCR yes 2u-EGF, u-IL6, u-IL8, u-MMP9NG, 3.68 (0.48) 0.48 (0.65) 0.32 (0.48) 2.52(0.65) 0.88 (0.13) u-NSE, u-VEGF, u-vWF OCR yes 3 u-CRP, u-IL1a, u-IL6,u-IL8, 3.36 (0.76) 0.28 (0.46) 0.64 (0.76) 2.72 (0.46) 0.87 (0.13)u-MMP9NG, u-NSE, u-VEGF age < 65 1 u-EGF, u-CRP, u-IL1b, u-IL2, 2.56(0.58) 0.36 (0.49) 0.44 (0.58) 4.64 (0.49) 0.89 (0.12) u-IL8, u-HA,u-CK18 age < 65 2 u-EGF, u-IL1b, u-IL4, u-IL8, 2.44 (0.58) 0.24 (0.44)0.56 (0.58) 4.76 (0.44) 0.88 (0.11) u-vWF, u-HA, u-CK18 age < 65 3u-EGF, u-IL1b, u-IL6, u-IL8, 2.44 (0.65) 0.36 (0.57) 0.56 (0.65) 4.64(0.57) 0.87 (0.13) u-MMP9, u-HA, u-CK18 CI no 1 u-EGF, u-CRP, u-IL4,u-MCP1, 1.72 (0.54) 0.36 (0.64) 0.28 (0.54) 3.64 (0.64) 0.88 (0.15)u-VEGF, u-FAS, u-CK18 CI no 2 u-dDimer, u-EGF, u-CRP, u-IL4, 1.76 (0.44)0.48 (0.59) 0.24 (0.44) 3.52 (0.59) 0.88 (0.14) u-IL6, u-sTNFR2, u-vWFCI no 3 u-dDimer, u-EGF, u-CRP, u-IL4, 1.6 (0.65) 0.2 (0.5) 0.4 (0.65)3.8 (0.5) 0.88 (0.21) u-IL6, u-sTNFR2, u-CK18 AC no 1 u-BTA, u-EGF,u-CRP, u-IL4, 4.28 (0.89) 0.76 (0.93) 0.72 (0.89) 5.24 (0.93) 0.86(0.11) u-sTNFR, u-HA, u-CK18 AC no 2 u-EGF, u-IL1a, u-IL1b, u-IL4, 3.96(1.14) 0.56 (0.77) 1.04 (1.14) 5.44 (0.77) 0.85 (0.14) u-sTNFR, u-VEGF,u-CK18 AC no 3 u-EGF, u-CRP, u-IL4, u-MMP9NG, 3.92 (0.76) 0.52 (0.59)1.08 (0.76) 5.48 (0.59) 0.85 (0.09) u-NGAL, u-HA, u-CK18 alcohol 1u-EGF, u-IL1a, u-IL6, u-NGAL, 3.52 (0.77) 1 (1) 0.48 (0.77) 4 (1) 0.84(0.13) yes u-sTNFR2, u-vWF, u-FAS alcohol 2 u-EGF, u-IL1a, u-IL2, u-IL6,3.36 (0.76) 0.84 (0.8) 0.64 (0.76) 4.16 (0.8) 0.84 (0.11) yes u-NGAL,u-VEGF, u-vWF alcohol 3 u-EGF, u-IL1a, u-NGAL, u-NSE, 3.52 (0.82) 1.04(0.89) 0.48 (0.82) 3.96 (0.89) 0.84 (0.12) yes u-sTNFR2, u-vWF, u-CK18AC yes 1 u-BTA, u-CRP, u-IL1b, u-IL8, 2.72 (0.46) 0.48 (0.65) 0.28(0.46) 1.52 (0.65) 0.83 (0.19) u-sTNFR2, u-vWF, u-FAS AC yes 2 u-dDimer,u-IL4, u-IL6, u-MMP9, 2.36 (0.76) 0.24 (0.44) 0.64 (0.76) 1.76 (0.44)0.83 (0.15) u-NSE, u-VEGF, u-CK18 AC yes 3 u-BTA, u-CRP, u-IL1a, u-IL2,2.88 (0.33) 0.6 (0.65) 0.12 (0.33) 1.4 (0.65) 0.83 (0.18) u-sTNFR2,u-vWF, u-FAS AH no 1 u-dDimer, u-CRP, u-IL2, u-NSE, 2.2 (0.71) 0.36(0.49) 0.8 (0.71) 4.64 (0.49) 0.83 (0.12) u-VEGF, u-vWF, u-CK18 AH no 2u-dDimer, u-CRP, u-IL2, u-NSE, 2.08 (0.81) 0.28 (0.61) 0.92 (0.81) 4.72(0.61) 0.82 (0.14) u-TNFa, u-VEGF, u-HA AH no 3 u-EGF, u-CRP, u-IL1a,u-IL1b, 2.04 (0.73) 0.28 (0.46) 0.96 (0.73) 4.72 (0.46) 0.81 (0.14)u-NGAL, u-VEGF, u-HA CI yes 1 u-BTA, u-IL2, u-MMP9NG, u-NGAL, 4.64(0.57) 0.84 (0.85) 0.36 (0.57) 2.16 (0.85) 0.82 (0.14) u-sTNFR, u-TNFa,u-VEGF CI yes 2 u-BTA, u-IL2, u-MMP9NG, u-TM, 4.4 (0.82) 0.88 (0.88) 0.6(0.82) 2.12 (0.88) 0.79 (0.14) u-sTNFR, u-vWF, u-FAS CI yes 3 u-BTA,u-IL2, u-MMP9NG, u-sTNFR, 4.36 (0.64) 0.88 (0.83) 0.64 (0.64) 2.12(0.83) 0.79 (0.13) u-VEGF, u-vWF, u-CK18 protein 1 u-dDimer, u-CRP,u-IL1a, u-IL4, 2.28 (0.79) 0.56 (0.65) 0.72 (0.79) 4.44 (0.65) 0.82(0.15) no u-MMP9NG, u-TM, u-CK18 protein 2 u-BTA, u-EGF, u-CRP, u-MMP9,2.28 (0.84) 0.68 (0.85) 0.72 (0.84) 4.32 (0.85) 0.81 (0.15) no u-NGAL,u-vWF, u-FAS protein 3 u-BTA, u-CRP, u-NGAL, u-NSE, 2.16 (0.9) 0.48(0.59) 0.84 (0.9) 4.52 (0.59) 0.81 (0.16) no u-TM, u-sTNFR2, u-vWFprotein 1 u-EGF, u-IL1b, u-IL2, u-NSE, 4.64 (0.57) 0.56 (0.65) 0.36(0.57) 1.44 (0.65) 0.82 (0.16) yes u-TM, u-VEGF, u-vWF protein 2 u-EGF,u-IL1b, u-MMP9, 4.56 (0.58) 0.56 (0.65) 0.44 (0.58) 1.44 (0.65) 0.82(0.17) yes u-MMP9NG, u-TNFa, u-vWF, u-HA protein 3 u-EGF, u-IL2, u-IL4,u-NGAL, 4.6 (0.5) 0.6 (0.76) 0.4 (0.5) 1.4 (0.76) 0.81 (0.19) yes u-NSE,u-TM, u-CK18 alcohol 1 u-IL1b, u-IL2, u-IL6, u-IL8, 3.04 (0.73) 0.4(0.58) 0.96 (0.73) 2.6 (0.58) 0.81 (0.13) no u-NGAL, u-NSE, u-CK18alcohol 2 u-IL1a, u-IL2, u-IL6, u-IL8, 3.16 (0.8) 0.52 (0.71) 0.84 (0.8)2.48 (0.71) 0.81 (0.16) no u-NGAL, u-HA, u-CK18 alcohol 3 u-BTA, u-IL1a,u-IL2, u-IL8, 3.16 (0.85) 0.52 (0.65) 0.84 (0.85) 2.48 (0.65) 0.81(0.15) no u-NGAL, u-VEGF, u-CK18 AH yes 1 u-CRP, u-IL1b, u-IL6, u-IL8,4.8 (0.41) 0.68 (0.69) 0.2 (0.41) 1.32 (0.69) 0.81 (0.18) u-MMP9,u-NGAL, u-vWF AH yes 2 u-dDimer, u-IL8, u-MMP9, u-NSE, 4.4 (0.87) 0.56(0.71) 0.6 (0.87) 1.44 (0.71) 0.8 (0.18) u-TM, u-sTNFR2, u-vWF AH yes 3u-BTA, u-dDimer, u-EGF, u-IL4, 4.6 (0.5) 0.64 (0.49) 0.4 (0.5) 1.36(0.49) 0.8 (0.14) u-NGAL, u-NSE, u-vWF age > 65 1 u-dDimer, u-CRP,u-IL1a, u-IL2, 4.36 (0.81) 0.76 (0.97) 0.64 (0.81) 2.24 (0.97) 0.81(0.19) u- u-NSE, u-vWF, u-vWF, u-HA age > 65 2 u-BTA, u-IL1a, u-IL8,u-MMP9NG, 4.56 (0.65) 0.92 (1) 0.44 (0.65) 2.08 (1) 0.8 (0.18) u-vWF,u-HA, u-CK18 age > 65 3 u-dDimer, u-IL1a, u-MCP1, u-NSE, 4.4 (0.71) 0.84(0.9) 0.6 (0.71) 2.16 (0.9) 0.8 (0.18) u-TNFa, u-vWF, u-HA smoking 1u-EGF, u-IL1a, u-MMP9, u-MMP9NG, 5.28 (0.98) 1.12 (0.88) 0.72 (0.98)2.88 (0.88) 0.8 (0.12) yes u-NSE, u-VEGF, u-vWF smoking 2 u-EGF, u-IL1b,u-NGAL, u-NSE, 5.36 (0.81) 1.2 (1) 0.64 (0.81) 2.8 (1) 0.8 (0.13) yesu-sTNFR, u-VEGF, u-vWF smoking 3 u-dDimer, u-EGF, u-IL1a, u-IL8, 5.08(0.76) 1.04 (0.89) 0.92 (0.76) 2.96 (0.89) 0.79 (0.12) yes u-NSE, u-vWF,u-FAS OCR no 1 u-BTA, u-dDimer, u-MMP9NG, 2.88 (0.93) 0.52 (0.65) 1.12(0.93) 3.48 (0.65) 0.8 (0.13) u-TM, u-TNFa, u-vWF, u-HA OCR no 2 u-IL6,u-NGAL, u-sTNFR, u-TNFa, 3.04 (0.84) 0.68 (0.75) 0.96 (0.84) 3.32 (0.75)0.8 (0.13) u-vWF, u-FAS, u-CK18 OCR no 3 u-BTA, u-IL1a, u-IL1b, u-IL6,2.88 (0.83) 0.56 (0.92) 1.12 (0.83) 3.44 (0.92) 0.79 (0.16) u-NGAL,u-TNFa, u-CK18

TABLE 11 Serum 7 biomarker classifiers name num Biomarker TP FP FN TNAUC smoking 1 s-CEA, s-EGF, s-CRP, s-IL4, 1.88 (0.33) 0.16 (0.37) 0.12(0.33) 2.84 (0.37) 0.94 (0.13) no s-IL8, s-NGAL, s-NSE smoking 2 s-CEA,s-IL6, s-IL8, s-Ifngg, 1.8 (0.41) 0.04 (0.2) 0.2 (0.41) 2.96 (0.2) 0.94(0.1) no s-NGAL, s-TM, s-VEGF smoking 3 s-CEA, s-FPSA, s-CRP, s-IL4,1.88 (0.44) 0.2 (0.41) 0.12 (0.44) 2.8 (0.41) 0.94 (0.12) no s-MMPNG,s-NGAL, s-TM age < 65 1 s-CEA, s-IL1a, s-IL2, s-IL4, 2.48 (0.65) 0.48(0.59) 0.52 (0.65) 4.52 (0.59) 0.87 (0.09) s-IL8, s-Ifngg, s-MMPNG age <65 2 s-CEA, s-EGF, s-FPSA, s-IL1a, 2.44 (0.58) 0.48 (0.65) 0.56 (0.58)4.52 (0.65) 0.86 (0.12) s-IL4, age < 65 3 s-IL8, s-VEGF 2.36 (0.91) 0.52(0.71) 0.64 (0.91) 4.48 (0.71) 0.84 (0.17) s-CEA, s-IL1a, s-IL2, s-IL8,s-Ifngg, s-MCP1, s-sTNFR OCR no 1 s-CEA, s-dDimer, s-IL4, s-IL10, 3.52(0.65) 0.72 (0.74) 0.48 (0.65) 3.28 (0.74) 0.85 (0.11) s-MCP1, s-MMPNG,s-NSE OCR no 2 s-CEA, s-dDimer, s-Ifngg, s-MCP1, 3.2 (0.76) 0.44 (0.51)0.8 (0.76) 3.56 (0.51) 0.84 (0.12) s-MMPNG, s-TM, s-TPSA OCR no 3 s-CEA,s-dDimer, s-EGF, s-IL6, 3.6 (0.5) 0.88 (1.01) 0.4 (0.5) 3.12 (1.01) 0.84(0.12) s-IL10, s-MMPNG, s-TM CI no 1 s-FPSA, s-IL2, s-IL4, s-IL6, 1.56(0.58) 0.36 (0.49) 0.44 (0.58) 3.64 (0.49) 0.84 (0.18) s-MMPNG, s-NGAL,s-sTNFR CI no 2 s-CEA, s-EGF, s-FPSA, s-CRP, 1.64 (0.49) 0.56 (0.71)0.36 (0.49) 3.44 (0.71) 0.84 (0.15) s-IL4, s-IL6, s-MMPNG CI no 3s-dDimer, s-IL1b, s-IL4, s-IL8, 1.44 (0.51) 0.2 (0.41) 0.56 (0.51) 3.8(0.41) 0.84 (0.14) s-MCP1, s-NGAL, s-TM alcohol 1 s-CEA, s-CRP, s-IL4,s-IL6, 3.36 (0.95) 0.48 (0.71) 0.64 (0.95) 2.52 (0.71) 0.84 (0.18) nos-IL10, s-sTNFR, s-TPSA alcohol 2 s-CEA, s-dDimer, s-EGF, s-IL1a, 3.28(0.79) 0.48 (0.59) 0.72 (0.79) 2.52 (0.59) 0.83 (0.12) no s-IL10, s-NSE,s-sTNFR alcohol 3 s-CEA, s-dDimer, s-IL1a, s-IL1b, 3.6 (0.58) 0.72(0.68) 0.4 (0.58) 2.28 (0.68) 0.83 (0.13) no s-IL4, s-TM, s-sTNFR AC yes1 s-FPSA, s-IL1b, s-IL10, s-NGAL, 2.52 (0.59) 0.32 (0.48) 0.48 (0.59)1.68 (0.48) 0.84 (0.13) s-TM, s-TNFa, s-VEGF AC yes 2 s-CEA, s-IL1b,s-IL4, s-NGAL, 2.4 (0.5) 0.4 (0.5) 0.6 (0.5) 1.6 (0.5) 0.8 (0.12) s-TM,s-TPSA, s-VEGF AC yes 3 s-FPSA, s-IL1b, s-IL4, s-IL10, 2.68 (0.56) 0.6(0.65) 0.32 (0.56) 1.4 (0.65) 0.8 (0.22) s-NGAL, s-TM, s-VEGF OCR yes 1s-FPSA, s-IL1b, s-IL2, s-IL4, 3.12 (0.73) 0.32 (0.56) 0.88 (0.73) 2.68(0.56) 0.84 (0.13) s-IL8, s-MMPNG, s-NGAL OCR yes 2 s-CEA, s-dDimer,s-IL8, s-IL10, 3.16 (0.9) 0.4 (0.65) 0.84 (0.9) 2.6 (0.65) 0.83 (0.16)s-Ifngg, s-NGAL, s-NSE OCR yes 3 s-CEA, s-EGF, s-CRP, s-IL10, 3.24(0.78) 0.48 (0.71) 0.76 (0.78) 2.52 (0.71) 0.82 (0.15) s-MCP1, s-NGAL,s-NSE AC no 1 s-CEA, s-IL1a, s-IL4, s-IL6, 4 (0.71) 0.8 (0.87) 1 (0.71)5.2 (0.87) 0.83 (0.11) s-IL8, s-TM, s-sTNFR AC no 2 s-CEA, s-IL1a,s-IL1b, s-IL4, 4.08 (0.7) 1 (0.91) 0.92 (0.7) 5 (0.91) 0.82 (0.11)s-IL8, s-MMPNG, s-VEGF AC no 3 s-CEA, s-IL1a, s-IL4, s-IL10, 3.88 (0.88)0.76 (0.97) 1.12 (0.88) 5.24 (0.97) 0.82 (0.1) s-MMPNG, s-TM, s-TNFaalcohol 1 s-EGF, s-CRP, s-IL8, s-MCP1, 3.24 (0.78) 0.76 (0.66) 0.76(0.78) 4.24 (0.66) 0.83 (0.12) yes s-MMPNG, s-NGAL, s-sTNFR alcohol 2s-CEA, s-EGF, s-CRP, s-IL1b, 3.16 (0.8) 0.72 (0.89) 0.84 (0.8) 4.28(0.89) 0.82 (0.11) yes s-MMPNG, s-NGAL, s-TM alcohol 3 s-CEA, s-dDimer,s-IL1a, s-IL2, 3.16 (0.8) 0.76 (0.78) 0.84 (0.8) 4.24 (0.78) 0.82 (0.11)yes s-IL4, s-IL10, s-NGAL protein 1 s-CEA, s-IL1b, s-IL2, s-IL4, 4.52(0.65) 0.52 (0.65) 0.48 (0.65) 1.48 (0.65) 0.82 (0.18) yes s-IL8, s-NSE,s-TNFa protein 2 s-CEA, s-EGF, s-IL4, s-IL8, 4.2 (0.87) 0.4 (0.5) 0.8(0.87) 1.6 (0.5) 0.82 (0.17) yes s-IL10, s-TPSA, s-VEGF protein 3 s-CEA,s-IL1b, s-IL2, s-IL4, 4.48 (0.65) 0.52 (0.51) 0.52 (0.65) 1.48 (0.51)0.82 (0.17) yes s-IL10, s-MMPNG, s-TM age > 65 1 s-CEA, s-dDimer,s-FPSA, s-CRP, 4.44 (0.87) 0.8 (0.76) 0.56 (0.87) 2.2 (0.76) 0.81 (0.15)s-IL10, s-NGAL, s-TM age > 65 2 s-CEA, s-dDimer, s-CRP, s-NGAL, 4.6(0.58) 0.96 (0.79) 0.4 (0.58) 2.04 (0.79) 0.8 (0.13) s-NSE, s-TM, s-TPSAage > 65 3 s-dDimer, s-IL1a, s-IL8, s-Ifngg, 4.28 (0.98) 0.8 (0.76) 0.72(0.98) 2.2 (0.76) 0.79 (0.12) s-MMPNG, s-NGAL, s-TM AH no 1 s-CEA,s-dDimer, s-EGF, s-IL4, 2.16 (0.75) 0.56 (0.65) 0.84 (0.75) 4.44 (0.65)0.8 (0.11) s-IL8, s-IL10, s-NSE AH no 2 s-CEA, s-dDimer, s-CRP, s-IL4,2.16 (0.69) 0.56 (0.77) 0.84 (0.69) 4.44 (0.77) 0.8 (0.13) s-MCP1,s-MMPNG, s-TNFa AH no 3 s-CEA, s-dDimer, s-CRP, s-IL4, 1.96 (1.06) 0.24(0.44) 1.04 (1.06) 4.76 (0.44) 0.8 (0.18) s-IL6, s-TM, s-TNFa protein 1s-FPSA, s-CRP, s-IL2, s-IL6, 2.08 (0.76) 0.48 (0.71) 0.92 (0.76) 4.52(0.71) 0.8 (0.12) no s-NGAL, s-TNFa, s-VEGF protein 2 s-CEA, s-FPSA,s-CRP, s-IL6, 1.96 (0.68) 0.44 (0.71) 1.04 (0.68) 4.56 (0.71) 0.78(0.13) no s-IL10, s-NGAL, s-VEGF protein 3 s-dDimer, s-FPSA, s-IL1b,s-Ifngg, 1.96 (0.89) 0.44 (0.58) 1.04 (0.89) 4.56 (0.58) 0.78 (0.14) nos-MMPNG, s-NGAL, s-TM AH yes 1 s-CEA, s-IL1a, s-IL1b, s-IL10, 4.08(1.08) 0.6 (0.65) 0.92 (1.08) 1.4 (0.65) 0.76 (0.22) s-NGAL, s-sTNFR,s-TNFa AH yes 2 s-CEA, s-IL1a, s-NGAL, s-NSE, 4.44 (0.77) 0.76 (0.6)0.56 (0.77) 1.24 (0.6) 0.75 (0.16) s-TM, s-TNFa, s-TPSA AH ys 3 s-CEA,s-IL1b, s-IL4, s-IL10, 4.4 (0.96) 0.76 (0.83) 0.6 (0.96) 1.24 (0.83)0.75 (0.2) s-MMPNG, s-NGAL, s-TM smoking 1 s-EGF, s-CRP, s-IL10,s-MMPNG, 5.08 (0.76) 1.44 (0.92) 0.92 (0.76) 2.56 (0.92) 0.74 (0.13) yess-NGAL, s-TM, s-VEGF smoking 2 s-CEA, s-CRP, s-IL10, s-MMPNG, 5.16 (0.9)1.68 (0.99) 0.84 (0.9) 2.32 (0.99) 0.72 (0.14) yes s-NGAL, s-TM, s-TNFasmoking 3 s-CEA, s-dDimer, s-IL2, s-IL8, 5.08 (1.15) 1.68 (0.85) 0.92(1.15) 2.32 (0.85) 0.71 (0.16) yes s-IL10, s-Ifngg, s-NSE CI yes 1s-CEA, s-CRP, s-IL1b, s-IL2, 4.76 (0.44) 1.4 (0.87) 0.24 (0.44) 1.6(0.87) 0.74 (0.16) s-TM, s-sTNFR, s-TPSA CI yes 2 s-CRP, s-IL1b, s-IL2,s-IL6, 4.68 (0.56) 1.36 (0.81) 0.32 (0.56) 1.64 (0.81) 0.74 (0.16)s-MMPNG, s-NGAL, s-TNFa CI yes 3 s-CRP, s-IL1b, s-IL2, s-MMPNG, 4.64(0.57) 1.36 (0.86) 0.36 (0.57) 1.64 (0.86) 0.74 (0.14) s-NGAL, s-NSE,s-TNFa

TABLE 12 Plasma 7 biomarker classifiers name num Biomarker TP FP FN TNAUC smoking 1 p-dDimer, p-EGF, p-IL1a, p-Ifng, 1.4 (0.58) 0.28 (0.54)0.6 (0.58) 2.72 (0.54) 0.8 (0.19) no p-MMPNG, p-TNFa, p-VEGF smoking 2p-EGF, p-IL1a, p-IL2, p-MMPNG, 1.48 (0.59) 0.48 (0.71) 0.52 (0.59) 2.52(0.71) 0.79 (0.2) no p-NGAL, p-NSE, p-TM smoking 3 p-IL1a, p-Ifng,p-MMPNG, p-NGAL, 1.24 (0.66) 0.2 (0.41) 0.76 (0.66) 2.8 (0.41) 0.78(0.18) no p-NSE, p-TM, p-TNFa OCR yes 1 p-IL1b, p-IL8, p-Ifng, p-MCP1,3.12 (0.83) 0.6 (0.71) 0.88 (0.83) 2.4 (0.71) 0.79 (0.16) p-MMPNG, p-TM,p-sTNFR OCR yes 2 p-IL1a, p-IL4, p-IL8, p-IL10, 2.8 (1) 0.48 (0.59) 1.2(1) 2.52 (0.59) 0.77 (0.18) p-MCP1, p-TM, p-sTNFR OCR yes 3 p-IL1a,p-IL1b, p-IL6, p-IL8, 2.88 (1.01) 0.56 (0.71) 1.12 (1.01) 2.44 (0.71)0.77 (0.13) p-NGAL, p-NSE, p-VEGF OCR no 1 p-IL4, p-IL6, p-IL10,p-MMPNG, 3.6 (0.65) 1.32 (0.75) 0.4 (0.65) 2.68 (0.75) 0.78 (0.09)p-NGAL, p-sTNFR, p-VEGF OCR no 2 p-dDimer, p-CRP, p-IL1a, p-IL1b, 3.48(0.59) 1.24 (0.93) 0.52 (0.59) 2.76 (0.93) 0.78 (0.13) p-IL2, p-IL4,p-MMPNG OCR no 3 p-dDimer, p-CRP, p-IL1b, p-IL4, 3.44 (0.71) 1.2 (0.96)0.56 (0.71) 2.8 (0.96) 0.78 (0.13) p-IL6, p-IL10, p-MMPNG CI no 1p-dDimer, p-IL1a, p-IL8, p-MMPNG, 1.2 (0.58) 0.32 (0.48) 0.8 (0.58) 3.68(0.48) 0.76 (0.16) p-TM, p-TNFa, p-VEGF CI no 2 p-dDimer, p-CRP, p-IL2,p-IL6, 1.28 (0.68) 0.52 (0.82) 0.72 (0.68) 3.48 (0.82) 0.76 (0.22)p-IL8, p-MMPNG, p-TNFa CI no 3 p-dDimer, p-IL1a, p-IL1b, p-IL8, 1.24(0.72) 0.44 (0.71) 0.76 (0.72) 3.56 (0.71) 0.76 (0.19) p-MMPNG, p-TM,p-VEGF AC yes 1 p-dDimer, p-EGF, p-IL6, p-IL1b, 2.36 (0.57) 0.6 (0.65)0.64 (0.57) 1.4 (0.65) 0.74 (0.19) p-Ifng, p-MCP1, p-TNFa AC yes 2p-dDimer, p-IL10, p-Ifng, p-MCP1, 2.16 (0.85) 0.52 (0.59) 0.84 (0.85)1.48 (0.59) 0.73 (0.2) p-NGAL, p-sTNFR, p-VEGF AC yes 3 p-dDimer, p-IL6,p-IL8, p-IL10, 2.24 (0.66) 0.6 (0.65) 0.76 (0.66) 1.4 (0.65) 0.72 (0.2)p-NSE, p-TM, p-TNFa age < 65 1 p-CRP, p-IL4, p-IL6, p-IL8, 1.8 (0.96)0.6 (0.58) 1.2 (0.96) 4.4 (0.58) 0.74 (0.19) p-IL10, p-MMPNG, p-TNFa age< 65 2 p-EGF, p-CRP, p-IL1b, p-IL8, 1.88 (0.97) 0.76 (0.83) 1.12 (0.97)4.24 (0.83) 0.74 (0.16) p-Ifng, p-NGAL, p-sTNFR age < 65 3 p-dDimer,p-EGF, p-CRP, p-IL8, 1.84 (0.9) 0.76 (0.78) 1.16 (0.9) 4.24 (0.78) 0.73(0.16) p-IL10, p-Ifng, p-MMPNG alcohol 1 p-IL1a, p-IL2, p-IL8, p-Ifng,3.52 (0.65) 1.2 (1) 0.48 (0.65) 1.8 (1) 0.74 (0.16) no p-MMPNG, p-sTNFR,p-TNFa alcohol 2 p-IL1a, p-IL2, p-IL6, p-IL10, 3.28 (0.84) 1.08 (0.86)0.72 (0.84) 1.92 (0.86) 0.73 (0.17) no p-MMPNG, p-TNFa, p-VEGF alcohol 3p-IL1a, p-IL4, p-IL6, p-IL10, 3.44 (0.87) 1.2 (0.71) 0.56 (0.87) 1.8(0.71) 0.73 (0.19) no p-MMPNG, p-NGAL, p-VEGF AH no 1 p-EGF, p-CRP,p-IL1a, p-IL8, 1.6 (0.76) 0.28 (0.46) 1.4 (0.76) 4.72 (0.46) 0.74 (0.13)p-MMPNG, p-TNFa, p-VEGF AH no 2 p-EGF, p-CRP, p-IL1b, p-IL8, 1.72 (0.79)0.6 (0.65) 1.28 (0.79) 4.4 (0.65) 0.73 (0.15) p-MMPNG, p-sTNFR, p-VEGFAH no 3 p-dDimer, p-EGF, p-IL1b, p-IL6, 1.8 (0.82) 0.8 (0.76) 1.2 (0.82)4.2 (0.76) 0.72 (0.14) p-IL8, p-MMPNG, p-VEGF AC no 1 p-IL1b, p-IL6,p-IL8, p-MMPNG, 3.44 (0.87) 1.28 (0.94) 1.56 (0.87) 4.72 (0.94) 0.74(0.11) p-sTNFR, p-TNFa, p-VEGF AC no 2 p-dDimer, p-IL1a, p-IL4, p-IL8, 3(1.19) 0.88 (0.88) 2 (1.19) 5.12 (0.88) 0.73 (0.12) p-NGAL, p-TM,p-sTNFR AC no 3 p-IL1a, p-IL1b, p-IL4, p-IL6, 3.76 (0.72) 1.88 (1.05)1.24 (0.72) 4.12 (1.05) 0.72 (0.13) p-IL8, p-MMPNG, p-sTNFR protein 1p-EGF, p-IL1a, p-IL2, p-IL4, 1.64 (0.86) 0.56 (0.77) 1.36 (0.86) 4.44(0.77) 0.72 (0.13) no p-MCP1, p-MMPNG, p-NGAL protein 2 p-dDimer, p-EGF,p-CRP, p-IL8, 1.76 (0.88) 0.84 (0.75) 1.24 (0.88) 4.16 (0.75) 0.71(0.17) no p-MMPNG, p-NSE, p-VEGF protein 3 p-dDimer, p-EGF, p-IL1b,p-IL8, 1.64 (0.76) 0.68 (0.75) 1.36 (0.76) 4.32 (0.75) 0.71 (0.14) nop-IL10, p-MMPNG, p-VEGF protein 1 p-IL1a, p-IL2, p-IL8, p-IL10, 4.64(0.64) 1 (0.76) 0.36 (0.64) 1 (0.76) 0.71 (0.19) yes p-Ifng, p-MCP1,p-TM protein 2 p-IL1a, p-IL2, p-IL8, p-Ifng, 4.48 (0.65) 1.04 (0.73)0.52 (0.65) 0.96 (0.73) 0.69 (0.21) yes p-MCP1, p-MMPNG, p-TM protein 3p-EGF, p-CRP, p-IL1a, p-IL4, 4.56 (0.51) 1.08 (0.57) 0.44 (0.51) 0.92(0.57) 0.69 (0.15) yes p-IL8, p-Ifng, p-TNFa age > 65 1 p-CRP, p-IL1a,p-IL10, p-MMPNG, 4.92 (0.28) 1.68 (0.75) 0.08 (0.28) 1.32 (0.75) 0.71(0.13) p-TM, p-TNFa, p-VEGF age > 65 2 p-IL1a, p-IL6, p-IL10, p-MMPNG,4.64 (0.57) 1.6 (0.76) 0.36 (0.57) 1.4 (0.76) 0.7 (0.14) p-TM, p-TNFa,p-VEGF age > 65 3 p-CRP, p-IL1a, p-IL4, p-IL6, 4.72 (0.54) 1.68 (0.85)0.28 (0.54) 1.32 (0.85) 0.69 (0.14) p-MMPNG, p-TM, p-TNFa alcohol 1p-dDimer, p-IL1b, p-IL4, p-MMPNG, 2.92 (0.95) 1.68 (1.03) 1.08 (0.95)3.32 (1.03) 0.7 (0.16) yes p-NGAL, p-NSE, p-VEGF alcohol 2 p-dDimer,p-IL1a, p-IL2, p-MMPNG, 2.56 (0.77) 1.44 (1.19) 1.44 (0.77) 3.56 (1.19)0.68 (0.12) yes p-NSE, p-sTNFR, p-TNFa alcohol 3 p-dDimer, p-CRP,p-IL1a, p-IL4, 2.56 (0.92) 1.48 (0.92) 1.44 (0.92) 3.52 (0.92) 0.67(0.15) yes p-IL10, p-NSE, p-sTNFR smoking 1 p-IL1a, p-IL1b, p-IL2,p-IL4, 5.28 (1.02) 2.04 (0.93) 0.72 (1.02) 1.96 (0.93) 0.68 (0.16) yesp-IL10, p-MMPNG, p-TNFa smoking 2 p-dDimer, p-IL1a, p-IL4, p-Ifng, 5.64(0.64) 2.32 (0.85) 0.36 (0.64) 1.68 (0.85) 0.68 (0.1) yes p-MCP1,p-MMPNG, p-TM smoking 3 p-dDimer, p-EGF, p-IL1a, p-IL4, 5.52 (0.59) 2.32(1.03) 0.48 (0.59) 1.68 (1.03) 0.67 (0.14) yes p-IL10, p-Ifng, p-MMPNGAH yes 1 p-dDimer, p-EGF, p-CRP, p-IL2, 4.76 (0.52) 1.36 (0.7) 0.24(0.52) 0.64 (0.7) 0.64 (0.17) p-IL10, p-MMPNG, p-TM AH yes 2 p-CRP,p-IL1a, p-IL1b, p-IL4, 4.8 (0.5) 1.44 (0.51) 0.2 (0.5) 0.56 (0.51) 0.62(0.12) p-IL6, p-Ifng, p-sTNFR AH yes 3 p-EGF, p-CRP, p-IL4, p-IL6, 4.48(0.71) 1.32 (0.69) 0.52 (0.71) 0.68 (0.69) 0.62 (0.14) p-IL10, p-Ifng,p-MMPNG CI yes 1 p-IL1a, p-IL8, p-IL10, p-MCP1, 4.68 (0.63) 2.08 (0.7)0.32 (0.63) 0.92 (0.7) 0.62 (0.13) p-MMPNG, p-NSE, p-TM CI yes 2p-dDimer, p-IL2, p-IL6, p-IL8, 4.68 (0.56) 2.12 (0.78) 0.32 (0.56) 0.88(0.78) 0.61 (0.14) p-MMPNG, p-TM, p-sTNFR CI yes 3 p-IL1a, p-IL2, p-IL6,p-IL8, 4.6 (0.58) 2.08 (0.76) 0.4 (0.58) 0.92 (0.76) 0.61 (0.15) p-MCP1,p-MMPNG, p-NSE

TABLE 13 Urine 7 biomarker classifiers Name Num Biomarker AUC Smoking no1 u-EGF(up), u-CRP(up), u-IL8(down), u-NGAL(down), u- 0.92 (0.1)NSE(up), u-TM(up), u-HA(down) Smoking no 2 u-BTA(down), u-EGF(up),u-IL8(down), u-MCP1(down), 0.89 (0.14) u-NGAL(down), u-NSE(up),u-sTNFR(up) Smoking no 3 u-BTA(down), u-IL4(down), u-MCP1(down),u-TM(up), 0.89 (0.12) u-sTNFR2(down), u-vWF(down), u-FAS(down) OCR yes 1u-EGF(up), u-IL1a(down), u-IL8(down), u-MMP9NG(up), 0.9 (0.1) u-NSE(up),u-vWF(down), u-CK18(down) OCR yes 2 u-EGF(up), u-IL6(down), u-IL8(down),u-MMP9NG(up), 0.88 (0.13) u-NSE(up), u-VEGF(down), u-vWF(down) OCR yes 3u-CRP(up), u-IL1a(down), n-IL6(down), u-IL8(down), u- 0.87 (0.13)MMP9NG(up), u-NSE(up), u-VEGF(down) age < 65 1 u-EGF(up), u-CRP(up),u-IL1b(down), u-IL2(down), u- 0.89 (0.12) IL8(down), u-HA(down),u-CK18(down) age < 65 2 u-EGF(up), u-IL1b(down), u-IL4(down),u-IL8(down), u- 0.88 (0.11) vWF(down), u-HA(down), u-CK18(down) age < 653 u-EGF(up), u-IL1b(down), u-IL6(down), u-IL8(down), u- 0.87 (0.13)MMP9(down), u-HA(down), u-CK18(down) CI no 1 u-EGF(up), u-CRP(up),u-IL4(down), u-MCP1(up), u- 0.88 (0.15) VEGF(down), u-FAS(down),u-CK18(up) CI no 2 u-dDimer(down), u-EGF(up), u-CRP(up), u-IL4(down),0.88 (0.14) u-IL6(down), u-sTNFR2(down), u-vWF(down) CI no 3u-dDimer(down), u-EGF(up), u-CRP(up), u-IL4(down), 0.88 (0.21)u-IL6(down), u-sTNFR2(down), u-CK18(up) AC no 1 u-BTA(down), u-EGF(up),u-CRP(up), u-IL4(down), u- 0.86 (0.11) sTNFR(up), u-HA(down), u-CK18(up)AC no 2 u-EGF(up), u-IL1a(down), u-IL1b(down), u-IL4(down), u- 0.85(0.14) sTNFR(up), u-VEGF(down), u-CK18(up) AC no 3 u-EGF(up), u-CRP(up),u-IL4(down), u-MMP9NG(up), u- 0.85 (0.09) NGAL(down), u-HA(down),u-CK18(up) Alcohol yes 1 u-EGF(up), u-IL1a(down), up-IL6(down),u-NGAL(down), 0.84 (0.13) u-sTNFR2(up), u-vWF(down), u-FAS(down) Alcoholyes 2 u-EGF(up), u-IL1a(down), u-IL2(down), u-IL6(down), u- 0.84 (0.11)NGAL(down), u-VEGF(down), u-vWF(down) Alcohol yes 3 u-EGF(up),u-IL1a(down), u-NGAL(down), u-NSE(up), 0.84 (0.12) u-sTNFR2(up),u-vWF(down), u-CK18(down) AC yes 1 u-BTA(down), u-CRP(up), u-IL1b(down),u-IL8(down), u- 0.83 (0.19) sTNFR2(down), u-vWF(down), u-FAS(down) ACyes 2 u-dDimer(down), u-IL4(up), u-IL6(down), u- 0.83 (0.15) MMP9(down),u-NSE(down), u-VFGF(down), u-CK18(up) AC yes 3 u-BTA(down), u-CRP(up),u-IL1a(down), u-IL2(down), u- 0.83 (0.18) sTNFR2(down), u-vWF(down),u-FAS(down) AH no 1 u-dDimer(down), u-CRP(up), u-IL2(down), u-NSE(up),0.83 (0.12) u-VEGF(down), u-vWF(down), u-CK18(down) AH no 2y-dDimer(down), u-CRP(up), u-IL2(down), u-NSE(up), 0.82 (0.14)u-TNFa(down), u-VEGF(down), u-HA(down) AH no 3 u-EGF(up), u-CRP(up),u-IL1a(down), u-IL1b(down), u- 0.81 (0.14) NGAL(down), u-VEGF(down),u-HA(down) CI yes 1 u-BTA(down), u-IL2(down), u-MMP9NG(down), u- 0.82(0.14) NGAL(down), u-sTNFR(down), u-TNFa(up), u-VEGF(down) CI yes 2u-BTA(down), u-IL2(down), u-MMP9NG(down), u- 0.79 (0.14) TM(down),u-sTNFR(down), u-vWF(down), u-FAS(down) CI yes 3 u-BTA(down),u-IL2(down), u-MMP9NG(down), u- 0.79 (0.13) sTNFR(down), u-VEGF(down),u-vWF(down), u-CK18(up) Protein no 1 u-dDimer(down), u-CRP(up),u-IL1a(down), u- 0.82 (0.15) IL4(down), u-MMP9MG(down), u-TM(up),u-CK18(up) Protein no 2 u-BTA(down), u-EGF(up), u-CRP(up), u-MMP9(down),0.81 (0.15) u-NGAL(up), u-vWF(down), u-FAS(down) Protein no 3u-BTA(down), u-CRP(up), u-NGAL(up), u-NSE(up), u- 0.81 (0.16) TM(up),u-TNFR2(down), u-vWF(down) Protein yes 1 u-EGF(down), u-IL1b(down),u-IL2(down), u-NSE(up), 0.82 (0.16) u-TM(down), u-VEGF(down),u-vWF(down) Protein yes 2 u-EGF(down), u-IL1b(down), u-MMP9(up), u- 0.82(0.17) MMP9NG(up), u-TNFa(up), u-vWF(down), uHA(down) Protein yes 3u-EGF(down), u-IL2(down), u-IL4(down), u- 0.81 (0.19) NGAL(down),u-NSE(up), u-TM(down), u-CK18(up) Alcohol no 1 u-IL1b(down),u-IL2(down), u-IL6(down), u-IL8(down), u- 0.81 (0.13) NGAL(down),u-NSE(up), u-CK18(up) Alcohol no 2 u-IL1a(down), u-IL2(down),u-IL6(down), u-IL8(down), u- 0.81 (0.16) NGAL(down), u-HA(down),u-CK18(up) Alcohol no 3 u-BTA(down), u-IL1a(down), u-IL2(down),u-IL8(down), 0.81 (0.15) u-NGAL(down), u-VEGF(down), u-CK18(up) AH yes 1u-CRP(up), u-IL1b(down), u-IL6(down), u-IL8(down), u- 0.81 (0.18)MMP9(up), u-NGAL(up), u-vWF(down) AH yes 2 u-dDimer(down), u-IL8(down),u-MMP9(up), u- 0.8 (0.18) NSE(down), u-TM(up), u-sTNFR2(down),u-vWF(down) AH yes 3 u-BTA(down), u-dDimer(down), u-EGF(down), u- 0.8(0.14) IL4(down), u-NGAL(up), u-NSE(down), u-vWF(down) Age > 65 1u-dDimer(down), u-CRP(down), u-IL1a(down), u- 0.81 (0.19) IL2(down),u-NSE(down), u-vWF(down), u-HA(up) Age > 65 2 u-BTA(down), u-IL1a(down),u-IL8(down), u- 0.8 (0.18) MMP9NG(up), u-vWF(down), u-HA(up), u-CK18(up)Age > 65 3 u-Dimer(down), u-IL1a(down), u-MCP1(down), u- 0.8 (0.18)NSE(down), u-TNFa(down), u-vWF(down), u-HA(up) Smoking yes 1 u-EGF(up),u-IL1a(down), u-MMP9(up), u-MMP9NG(up), 0.8 (0.12) u-NSE(down),u-VEGF(down), u-vWF(down) Smoking yes 2 u-EGF(up), u-IL1b(down),u-NGAL(down), u-NSE(down), 0.8 (0.13) u-sTNFR(up), u-VEGF(down),u-vWF(down) Smoking yes 3 u-dDimer(down), u-EGF(up), u-IL1a(down), u-0.79 (0.12) IL8(down), u-NSE(down), u-vWF(down), u-FAS(down) OCR no 1u-BTA(down), u-dDimer(down), u-MMP9NG(up), u- 0.8 (0.13) TM(up),u-TNFa(down), u-vWF(down), u-HA(down) OCR no 2 u-IL6(-(down) u-NGAL(up),u-TNFR(down), u- 0.8 (0.13) TNFa(down), u-vWF(down), u-FAS(down),u-CK18(up) OCR no 3 u-BTA(down), u-IL1a(down), u-IL1b(down),u-IL6(down), 0.79 (0.16) u-NGAL(up), u-TNFa(down), u-CK18(up)

TABLE 14 Plasma biomarker classifiers name num Biomarker AUC smoking no1 p-dDimer(down), p-EGF(down), p-IL1a(down), p-Ifng(down), 0.8 (0.19)p-MMPNG(down), p-TNFa(down), p-VEGF(up) smoking no 2 p-EGF(down),P-IL1a(down), p-IL2(down), p-MMPNG(down), 0.79 (0.2) p-NGAL(down),p-NSE(up), p-TM(down) smoking no 3 p-IL1a(down), p-IFng(down),p-MMPNG(down), p- 0.78 (0.18) NGAL(down), p-NSE(up), p-TM(down),p-TNFa(down) OCR yes 1 p-IL1b(up), p-IL8(down), p-Ifng(down),p-MCP1(down), p- 0.79 (0.16) MMPNG(down), p-TM(down), p-sTNFR(up) OCRyes 2 p-IL1a(down), p-IL4(down), p-IL8(down), p-IL10(down), p- 0.77(0.18) MCP1(down), p-TM(down), p-sTNFR(up) OCR yes 3 p-IL1a(down),p-IL1b(up), p-IL6(down), p-IL8(down), p- 0.77 (0.13) NGAL(down),p-NSE(down), p-VEGF(down) OCR no 1 p-IL4(up), p-IL6(down), p-IL10(down),p-MMPNG(down), p- 0.78 (0.09) NGAL(up), p-sTNFR(up), p-VEGF(up) OCR no 2p-dDimer(down), p-CRP(up), p-IL1a(down), p-IL1b(down), p- 0.78 (0.13)IL2(down), p-IL4(up), p-MMPNG(down) OCR no 3 p-dDimer(down), p-CRP(up),p-IL1b(down), p-IL4(up), p- 0.78 (0.13) IL6(down), p-IL10(down),p-MMPNG(down) CI no 1 p-dDimer(down), p-IL1a(up), p-IL8(up),p-MMPNG(down), p- 0.76 (0.16) TM(down), p-TNFa(down), p-VEGF(up) CI no 2p-dDimer(down), p-CRP(down), p-IL2(down), p-IL6(down), p- 0.76 (0.22)IL8(up), p-MMPNG(down), p-TNFa(down) CI no 3 p-dDimer(down), p-IL1a(up),p-IL1b(down), p-IL8(up), p- 0.76 (0.19) MMPNG(down), p-TM(down),p-VEGF(up) AC yes 1 p-dDimer(up), p-EGF(up), p-IL6(down), p-IL10(down),p- 0.74 (0.19) Ifng(down), p-MCP1(down), p-TNFa(down) AC yes 2p-dDimer(up), p-IL10(down), p-Ifng(down), p-MCP1(down), p- 0.73 (0.2)NGAL(up), p-sTNFR(down), p-VEGF(up) AC yes 3 p-dDimer(up), p-IL6(down),p-IL8(down), p-IL10(down), p- 0.72 (0.2) NSE(up), p-TM(down),p-TNFa(down) age < 65 1 p-CRP(up), p-IL4(up), P-IL6(down), p-IL8(down),p- 0.74 (0.19) IL10(down), p-MMPNG(down), p-TNFa(down) age < 65 2p-EGF(down), p-CRP(up), p-IL1b(down), p-IL8(down), p- 0.74 (0.16)Ifng(down), p-NGAL(down), p-sTNFR(up) age < 65 3 p-dDimer(down),p-EGF(down), p-CRP(up), p-IL8(down), p- 0.73 (0.16) IL10(down),p-Ifng(down), p-MMPNG(down) alcohol no 1 p-IL1a(up), p-IL2(down),p-IL8(down), p-Ifng(down), p- 0.74 (0.16) MMPNG(down), p-sTNFR(up),p-TNFa(down) alcohol no 2 p-IL1a(up), p-IL2(down), p-IL6(down),p-IL10(down), p- 0.73 (0.17) MMPNG(down), p-TNFa(down), p-VEGF(down)alcohol no 3 p-IL1a(up), p-IL4(up), p-IL6(down), p-IL10(down), p- 0.73(0.19) MMPNG(down), p-NGAL(down), p-VEGF(down) AH no 1 p-EGF(down),p-CRP(up), p-IL1a(down), p-IL8(down), p- 0.74 (0.13) MMPNG(down),p-TNFa(up), p-VEGF(up) AH no 2 p-EGF(down), p-CRP(up), p-IL1b(up),p-IL8(down), p- 0.73 (0.15) MMPNG(down), p-sTNFR(up), p-VEGF(up) AH no 3p-dDimer(down), p-EGF(down), p-IL1b(up), p-IL6(down), p- 0.72 (0.14)IL8(down), p-MMPNG(down), p-VEGF(up) AC no 1 p-IL1b(down), p-IL6(down),p-IL8(down), p-MMPNG(down), 0.74 (0.11) p-sTNFR(up), p-TNFa(down),p-VEGF(down) AC no 2 p-dDimer(down), p-IL1a(down), p-IL4(up),p-IL8(down), p- 0.73 (0.12) NGAL(down), p-TM(down), p-sTNFR(up) AC no 3p-IL1a(down), p-IL1b(down), p-IL4(up), p-IL6(down), p- 0.72 (0.13)IL8(down), p-MMPNG(down), p-sTNFR(up) protein no 1 p-EGF(down),p-IL1a(down), p-IL2(down), p-IL4(up), p- 0.72 (0.13) MCP1(up),p-MMPNG(down), p-NGAL(down) protein no 2 p-dDimer(down), p-EGF(down),p-CRP(down), p-IL8(up), p- 0.71 (0.17) MMPNG(down), p-NSE(up),p-VEGF(down) protein no 3 p-dDimer(down), p-EGF(down), p-IL1b(down),p-IL8(up), p- 0.71 (0.14) IL10(down), p-MMPNG(down), p-VEGF(down)protein yes 1 p-IL1a(down), p-IL2(up), p-IL8(down), p-IL10(down), p-0.71 (0.19) Ifng(down), p-MCP1(down), p-TM(down) protein yes 2p-IL1a(down), p-IL2(up), p-IL8(down), p-Ifng(down), p- 0.69 (0.21)MCP1(down), p-MMPNG(down), p-TM(down) protein yes 3 p-EGF(up),p-CRP(up), p-IL1a(down), p-IL4(up), p- 0.69 (0.13) IL8(down),p-Ifng(down), p-TNFa(down) age > 65 1 p-CRP(down), p-IL1a(up),p-IL10(down), p-MMPNG(down), 0.71 (0.13) p-TM(down), p-TNFa(up),p-VEGF(down) age > 65 2 p-IL1a(up), p-IL6(down), p-IL10(down),p-MMPNG(down), p- 0.7 (0.14) TM(down), p-TNFa(up), p-VEGF(down) age > 653 p-CRP(down), p-IL1a(up), p-IL4(up), p-IL6(down), p- 0.69 (0.14)MMPNG(down), p-TM(down), p-TNFa(up) alcohol yes 1 p-dDimer(down),p-IL1b(down), p-IL4(up), p-MMPNG(down), 0.7 (0.16) p-NGAL(down),p-NSE(up), p-VEGF(up) alcohol yes 2 p-dDimer(down), p-IL1a(up),p-IL2(down), p-MMPNG(down), 0.68 (0.12) p-NSE(up), p-sTNFA(up),p-TNFa(down) alcohol yes 3 p-dDimer(down), p-CRP(up), p-IL1a(up),p-IL4(up), p- 0.67 (0.15) IL10(down), p-NSE(up), p-sTNFR(up) smoking yes1 p-IL1a(down), p-IL1b(up), p-IL2(up), p-IL4(up), p- 0.68 (0.16)IL10(down), p-MMPNG(down), p-TNFa(down) smoking yes 2 p-dDimer(down),p-IL1a(down), p-IL4(up), p-Ifng(up), p- 0.68 (0.1) MCP1(down),p-MMPNG(down), p-TM(down) smoking yes 3 p-dDimer(down), p-EGF(up),p-IL1a(down), p-IL4(up), p- 0.67 (0.14) IL10(down), p-Ifng(up),p-MMPNG(down) AH yes 1 p-dDimer(up), p-EGF(up), p-CRP(down),p-IL2(down), p- 0.64 (0.17) IL10(down), p-MMPNG(down), p-TM(down) AH yes2 p-CRP(down), p-IL1a(down), p-IL1b(down), p-IL4(up), p- 0.62 (0.12)IL6(down), p-Ifng(down), p-sTNFR(up) AH yes 3 p-EGF(up), p-CRP(down),p-IL4(up), p-IL6(down), p- 0.62 (0.14) IL10(down), p-Ifng(down),p-MMPNG(down) CI yes 1 p-IL1a(down), p-IL8(down), p-IL10(down),p-MCP1(down), p- 0.62 (0.13) MMPNG(down), p-NSE(up), p-TM(down) CI yes 2p-dDimer(down), p-IL2(down), p-IL6(up), p-IL8(down), p- 0.61 (0.14)MMPNG(down), p-TM(down), p-sTNFR(up) CI yes 3 p-IL1a(down), p-IL2(down),p-IL6(up), p-IL8(down), p- 0.61 (0.15) MCP1(down), p-MMPNG(down),pNSE(up)

TABLE 15 Serum 7 biomarker classifiers name num Biomarker AUC smoking no1 s-CEA(up), s-EGF(down), s-CRP(down), s-IL4(up), s-IL8(down), 0.94(0.13) s-NGAL(down), s-NSE(down) smoking no 2 s-CEA(up), s-IL6(down),s-IL8(down), s-Ifngg(down), s- 0.94 (0.1) NGAL(down), s-TM(down),s-VEGF(up) smoking no 3 s-CEA(up), s-FPSA(up), s-CRP(down), s-IL4(up),s- 0.94 (0.12) MMPNG(down), s-NGAL(down), s-TM(down) age < 65 1s-CEA(down), s-IL1a(up), s-IL2(down), s-IL4(up), s-IL8(down), s- 0.87(0.09) Ifngg(down), s-MMPNG(down) age < 65 2 s-CEA(down), s-EGF(down),s-FPSA(up), s-IL1a(up), s-IL4(up), s- 0.86 (0.12) IL8(down), s-VEGF(up)age < 65 3 s-CEA(down), s-IL1a(up), s-IL3(down), s-IL8(down), s- 0.84(0.17) Ifngg(down), s-MCP1(down), s-sTNFR(up) OCR no 1 s-CEA(down),s-dDimer(down), s-IL4(up) s-IL10(down), s- 0.83 (0.11) MCP1(up),s-MMPNG(down), s-NSE(up) OCR no 2 s-CEA(down), s-dDimer(down),s-Ifngg(down), s-MCP1(up), s- 0.84 (0.12) MMPNG(down), s-TM(up),s-TPSA(up) OCR no 3 s-CEA(down), s-dDimer(down), s-EGF(up), s-IL6(down),s- 0.84 (0.12) IL10(down), s-MMPNG(down), s-TM(up) CI no 1 s-FPSA(up),s-IL2(down), s-IL4(up), s-IL6(down), s- 0.84 (0.18) MMPNG(down),s-NGAL(down), s-sTNFR(up) CI no CI 2 s-CEA(down), s-EGF(up), s-FPSA(up),s-CRP(down), s-IL4(up), s- 0.84 (0.15) IL6(down), s-MMPNG(down) noalcohol 3 s-dDimer(down), s-IL1b(down), s-IL4(up), s-IL8(down), s- 0.84(0.14) MCP1(up), s-NGAL(down), s-TM(up) no alcohol 1 s-CEA(down),s-CRP(down), s-IL4(up), s-IL6(down), s- 0.84 (0.18) IL10(down),s-sTNFR(up), s-TPSA(up) no alcohol 2 s-CEA(down), s-dDimer(down),s-EGF(down), s-IL1a(up), s- 0.83 (0.12) IL10(down), s-NSE(down),s-sTNFR(up) no AC yes 3 s-CEA(down), s-dDimer(down), s-IL1a(up),s-IL1b(up), s-IL4(up), 0.83 (0.13) s-TM(down), s-sTNFR(up) AC yes 1s-FPSA(up), s-IL1b(down), s-IL10(down), s-NGAL(down), s- 0.84 (0.13)TM(up), s-TNFa(down), s-VEGF(up) AC yes 2 s-CEA(down), s-IL1b(down),s-IL4(up), s-NGAL(down), s- 0.8 (0.12) TM(up), s-TPSA(up), s-VEGF(up)OCR yes 3 s-FPSA(up), s-IL1b(down), s-IL4(up), s-IL10(down), s- 0.8(0.22) NGAL(down), s-TM(up), s-VEGF(up) OCR yes 1 s-FPSA(up),s-IL1b(up), s-IL2(up), s-IL4(up), s-IL8(down), s- 0.84 (0.13)MMPNG(down), s-NGAL(down) OCR yes 2 s-CEA(down), s-dDimer(down),s-IL8(down), s-IL10(up), s- 0.83 (0.16) Ifngg(up), s-NGAL(down),s-NSE(down) AC no 3 s-CEA(down), s-EGF(down), s-CRP(down), s-IL10(up),s- 0.82 (0.15) MCP1(down), s-NGAL(down), s-NSE(down) AC no 1s-CEA(down), s-IL1a(up), s-IL4(up), s-IL6(down), s-IL8(down), s- 0.83(0.11) TM(down), s-sTNFR(up) AC no 2 s-CEA(down), s-IL1a(up),s-IL1b(down), s-IL4(up), s-IL8(down), 0.82 (0.11) s-MMPNG(down),s-VEGF(down) alcohol yes 3 s-CEA(down), s-IL1a(up), s-IL4(up),s-IL10(down), s- 0.82 (0.1) MMPNG(down), s-TM(down), s-TNFa(down)alcohol yes 1 s-EGF(up), s-CRP(up), s-IL8(down), s-MCP1(down), s- 0.83(0.12) MMPNG(down), s-NGAL(down), s-sTNFR(up) alcohol yes 2 s-CEA(down),s-EGF(up). s-CRP(up), s-IL1b(down), s- 0.82 (0.11) MMPNG(down),s-NGAL(down), s-TM(down) protein yes 3 s-CEA(down), s-dDimer(down),s-IL1a(up), s-IL2(up), s-IL4(up), 0.82 (0.11) s-IL10(down), s-NGAL(down)protein yes 1 s-CEA(down), s-IL1b(up), s-IL2(up), s-IL4(up),s-IL8(down), s- 0.82 (0.18) NSE(down), s-TNFa(down) protein yes 2s-CEA(down), s-EGF(down), s-IL4(up), s-IL8(down), s- 0.82 (0.17)IL10(down), s-TPSA(up), s-VEGF(up) age > 65 3 s-CEA(down), s-IL1b(up),s-IL2(up), s-IL4(up), s-IL10(down), s- 0.82 (0.17) MMPNG(down),s-TM(down) age > 65 1 s-CEA(down), s-dDimer(down), s-FPSA(up),s-CRP(down), s- 0.81 (0.15) IL10(down), s-NGAL(down), s-TM(down) age >65 2 s-CEA(down), s-dDimer(down), s-CRP(down), s-NGAL(down), s- 0.8(0.13) NSE(down), s-TM(down), s-TPSA(up) AH no 3 s-dDimer(down),s-IL1a(up), s-IL8(up), s-Ifngg(up), s- 0.79 (0.12) MMPNG(down),s-NGAL(down), s-TM(down) AH no 1 s-CEA(down), s-dDimer(down),s-EGF(down) s-IL4(up), s- 0.8 (0.11) IL8(down), s-IL10(up), s-NSE(down)AH no 2 s-CEA(down), s-dDImer(down), s-CRP(up), s-IL4(up), s- 0.8 (0.13)MCP1(down), s-MMPNG(down), s-TNFa(up) protein no 3 s-CEA(down),s-dDimer(down), s-CRP(up), s-IL4(up), s- 0.8 (0.18) IL6(down),s-TM(down), s-TNFa(up) protein no 1 s-FPSA(up), s-CRP(down),s-IL2(down), s-IL6(down), s- 0.8 (0.12) NGAL(down), s-TNFa(down),s-VEGF(down) protein no 2 s-CEA(down), s-FPSA(up), s-CRP(down),s-IL6(down), s- 0.78 (0.13) IL10(down), s-NGAL(down), s-VEGF(down) AHyes 3 s-dDimer(down), s-FPSA(up), s-IL1b(down), s-Ifngg(up), s- 0.78(0.14) MMPNG(down), s-NGAL(down), s-TM(up) AH yes 1 s-CEA(down),s-IL1a(down), s-IL1b(down), s-IL10(down), s- 0.76 (0.22) NGAL(down),s-sTNFR(up), s-TNFa(down) AH yes 2 s-CEA(down), s-IL1a(down),s-NGAL(down), s-NSE(down), s- 0.75 (0.16) TM(down), s-TNFa(down),s-TPSA(up) smoking yes 3 s-CEA(down), s-IL1b(down), s-IL4(up),s-IL10(down), s- 0.75 (0.3) MMPNG(down), s-NGAL(down), s-TM(down)smoking yes 1 s-EGF(up), s-CRP(down), s-IL10(down), s-MMPNG(down), s-0.74 (0.13) NGAL(down), s-TM(down), s-VEGF(down) smoking yes 2s-CEA(down), s-CRP(down), s-IL10(down), s-MMPNG(down), s- 0.72 (0.14)NGAL(down), s-TM(down) s-TNFa(down) CI yes 3 s-CEA(down),s-dDimer(down), s-IL2(up), s-IL8(down), s- 0.71 (0.16) IL10(down),s-Ifngg(up), s-NSE(down) CI yes 1 s-CEA(down), s-CRP(down),s-IL1b(down), s-IL2(up), s- 0.74 (0.16) TM(down), s-sTNFR(up),s-TPSA(down) CI yes 2 s-CRP(down), s-IL1b(down), s-IL2(up), s-IL6(up),s- 0.74 (0.16) MMPNG(down), s-NGAL(down), s-TNFa(up) 3 s-CRP(down),s-IL1b(down), s-IL2(up), s-MMPNG(down), s- 0.74 (0.14) NGAL(down),s-NSE(down), s-TNFa(up)

TABLE 16 Urine 7 biomarker urothelial cancer (UC) classifiers. Inparenthesis the pattern for up or down regulation of a biomarker in UCare shown. name num Biomarker AUC smoking no 1 u-EGF(down), u-CRP(down),u-IL8(up), u-NGAL(up), u- 0.92 (0.1) NSE(down), u-TM(down), u-HA(up)smoking no 2 u-BTA(up), u-EGF(down), u-IL8(up), u-MCP1(up), u-NGAL(up),u- 0.89 (0.14) NSE(down), u-sTNFR(down) smoking no 3 u-BTA(up),u-IL4(up), u-MCP1(up), u-TM(down), u-sTNFR2(up), u- 0.89 (0.12) vWF(up),u-FAS(up) OCR yes 1 u-EGF(down), u-IL1a(up), u-IL8(up), u-MMP9NG(down),u- 0.9 (0.1) NSE(down), u-vWF(up), u-CK18(up) OCR yes 2 u-EGF(down),u-IL6(up), u-IL8(up), u-MMP9NG(down), u- 0.88 (0.13) NSE(down),u-VEGF(up), u-vWF(up) OCR yes 3 u-CRP(down), u-IL1a(up), u-IL6(up),u-IL8(up), u- 0.87 (0.13) MMP9NG(down), u-NSE(down), u-VEGF(up) age < 651 u-EGF(down), u-CRP(down), u-IL1b(up), u-IL2(up), u-IL3(up), u- 0.89(0.12) HA(up), u-CK18(up) age < 65 2 u-EGF(down), u-IL1b(up), u-IL4(up),u-IL8(up), u-vWF(up), u- 0.88 (0.11) HA(up), u-CK18(up) age < 65 3u-EGF(down), u-IL1b(up), u-IL6(up), u-IL8(up), u-MMP9(up), u- 0.87(0.13) HA(up), u-CK18(up) CI no 1 u-EGF(down), u-CRP(down) u-IL4(up),u-MCP1(down), u- 0.88 (0.15) VEGF(up), u-FAS(up), u-CK18(down) CI no 2u-dDimer(up), u-EGF(down), u-CRP(down), u-IL4(up), u-IL6(up), u- 0.88(0.14) sTNFR2(up), u-vWF(up) CI no 3 u-dDimer(up), u-EGF(down),u-CRP(down), u-IL4(up), u-IL6(up), u- 0.88 (0.21) sTNFR2(up),u-CK18(down) AC no 1 u-BTA(up), u-EGF(down), u-CRP(down), u-IL4(up), u-0.86 (0.14) sTNFR(down), u-HA(up), u-CK18(down) AC no 2 u-EGF(down),u-IL1a(up), u-IL1b(up), u-IL4(up), u-sTNFA(down), u- 0.85 (0.14)VEGF(up), u-CK18(down) AC no 3 u-EGF(down), u-CRP(down), u-IL4(up),u-MMP9NG(down), u- 0.85 (0.09) NGAL(up), u-HA(up), u-CK18(down) alcoholyes 1 u-EGF(down), u-IL1a(up), u-IL6(up), u-NGAL(up), u- 0.84 (0.13)sTNFR2(down), u-vWF(up), u-FAS(up) alcohol yes 2 u-EGF(down),u-IL1a(up), u-IL2(up), u-IL6(up), u-NGAL(up), u- 0.84 (0.11) VEGF(up),u-vWF(up) alcohol yes 3 u-EGF(down), u-IL1a(up), u-NGAL(up),u-NSE(down), u- 0.84 (0.12) sTNFR2(down), u-vWF(up), u-CK18(up) AC yes 1u-BTA(up), u-CRP(down), u-IL1b(up), u-sTNFR2(up), u- 0.83 (0.19)vWF(up), u-FAS(up) AC yes 2 u-dDimer(up), u-IL4(down), u-IL69up),u-MMP9(up), u-NSE(up), u- 0.83 (0.15) VEGF(up), u-CK18(down) AC yes 3u-BTA(up), u-CRP(down), u-IL1a(up), u-IL2(up), u-sTNFR2(up), u- 0.83(0.18) vWF(up), u-FAS(up) AH no 1 u-dDimer(up), u-CRP(down), u-IL2(up),u-NSE(down) u- 0.83 (0.12) VEGF(up), u-vWF(up), u-CK18(up) AH no 2u-dDimer(up), u-CRP(down), u-IL2(up), u-NSE(down), u- 0.82 (0.14)TNFa(up), u-VEGF(up), u-HA(up) AH no 3 u-EGF(down), u-CRP(down),u-IL1a(up), u-IL1b(up), u- 0.81 (0.14) NGAL(up), u-VEGF(up), u-HA(up) CIyes 1 u-BTA(up), u-IL2(up), u-MMP9NG(up), u-NGAL(up), u- 0.82 (0.14)sTNFR(up), u-TNFa(down), u-VEGF(up) CI yes 2 u-BTA(up), u-IL2(up),u-MMP9NG(up), u-TM(up), u-sTNFR(up), u- 0.79 (0.14) vWF(up), u-FAS(up)CI yes 3 u-BTA(up), u-IL2(up), u-MMP9NG(up), u-VEGF(up), u- 0.79 (0.13)vWF(up), u-CK18(down) protein no 1 u-dDimer(up), u-CRP(down),u-IL1a(up), u-IL4(up), u- 0.82 (0.15) MMP9NG(up), u-TM(down),u-CK18(down) protein no 2 u-MTA(up), u-EGF(down), u-CRP(down),u-MMP9(up, u- 0.81 (0.15) NGAL(down), u-vWF(up), u-FAS(up) protein no 3u-BTA(up), u-CRP(down), u-NGAL(down), u-NSE(down), u- 0.81 (0.16)TM(down), u-sTNFR2(up), u-vWF(up) protein yes 1 u-EGF(up), u-IL1b(up),u-IL2(up), u-NSE(down), u-TM(up), u- 0.82 (0.16) VEGF(up), u-vWF(up)protein yes 2 u-EGF(up), u-IL1b(up), u-MMP9(down), u-MMP9NG(down), u-0.82 (0.17) TNFa(down), u-vWF(up), u-HA(up) protein yes 3 u-EGF(up),u-IL2(up), u-IL4(up), u-NGAL(up), u-NSE(down), u- 0.81 (0.19) TM(up),u-CK18(down) alcohol no 1 u-IL1b(up), u-IL2(up), u-IL6(up), u-IL8(up),u-NGAL(up), u- 0.81 (0.13) NSE(down), u-CK18(down) alcohol no 2u-IL1a(up), u-IL2(up), u-IL6(up), u-IL8(up), u-NGAL(up), u- 0.81 (0.16)HA(up), u-CK18(down) alcohol no 3 u-BTA(up), u-IL1a(up), u-IL2(up),u-IL8(up), u-NGAL(up), u- 0.81 (0.15) VEGF(up), u-CK18(down) AH yes 1u-CRP(down), u-IL1b(up), u-IL6(up), u-IL8(up), u-MMP9(down), u- 0.81(0.18) NGAL(down), u-vWF(up) AH yes 2 u-dDimer(up), u-IL8(up),u-MMP9(down), u-NSE(up), u- 0.8 (0.18) TM(down), u-sTNFA2(up), u-vWF(up)AH yes 3 u-BTA(up), u-dDimer(up), u-EGF(up), u-IL4(up), u-NGAL(down), u-0.8 (0.14) NSE(up), u-vWF(up) age > 65 1 u-dDimer(up), u-CRP(up),u-IL1a(up), u-IL2(up), u-NSE(up), u- 0.81 (0.19) vWF(up), u-HA(down)age > 65 2 u-BTA(up), u-IL1a(up), u-IL8(up), u-MMP9NG(down), u- 0.8(0.18) vWF(up), u-HA(down), u-CK18(down) age > 65 3 u-dDimer(up),u-IL1a(up), u-MCP1(up), u-NSE(up), u-TNFa(up), u- 0.8 (0.18) vWF(up),u-HA(down) smoking yes 1 u-EGF(down), u-IL1a(up), u-MMP9(down),u-MMP9NG(down), u- 0.8 (0.12) NSE(up), u-VEGF(up), u-vWF(up) smoking yes2 u-EGF(down), u-IL1b(up), u-NGAL(up), u-sTNFR(down), u- 0.8 (0.13)VEGF(up), u-vWF(up) smoking yes 3 u-dDimer(up), u-EGF(down), u-IL1a(up),u-IL8(up), u-NSE(up), u- 0.79 (0.12) vWF(up), u-FAS(up) OCR no 1u-BTA(up), u-dDimer(up), u-MMP9NG(down), u-TM(down), u- 0.8 (0.13)TNFa(up), u-vWF(up), u-HA(up) OCR no 2 u-IL6(up), u-NGAL(down),u-sTNFR(up), u-TNFa(up), u- 0.8 (0.13) vWF(up), u-FAS(up), u-CK18(down)OCR no 3 u-BTA(up), u-IL1a(up), u-IL1b(up), u-IL6(up), u-NGAL(down), u-0.79 (0.16) TNFa(up), u-CK18(down)

TABLE 17 Serum 7 biomarker urothelial cancer (UC) classifiers. Inparenthesis the pattern for up or down regulation of a biomarker in UCare shown. name num Biomarker AUC smoking no 1 s-CEA(down), s-EGF(up),s-CRP(up), s-IL4(down), s-IL8(up), s- 0.94 (0.13) NGAL(up), s-NSE(up)smoking no 2 s-CEA(down), s-IL6(up), s-IL8(up), s-Ifngg(up), s-NGAL(up),s- 0.94 (0.1) TM(up, s-VEGF(down) smoking no 3 s-CEA(down),s-FPSA(down), s-CRP(up), s-IL4(down), s- 0.94 (0.12) MMPNG(up),s-NGAL(up), s-TM(up) age < 65 1 s-CEA(up), s-IL1a(down), s-IL2(up),s-IL4(down), s-IL8(up), s- 0.87 (0.09) Ifngg(up), s-MMPNG(up) age < 65 2s-CEA(up), s-EGF(up), s-FPSA(down), s-IL1a(down), s- 0.86 (0.12)IL4(down), s-IL8(up), s-VEGF(down) age < 65 3 s-CEA(up), s-IL1a(down),s-IL2(up), s-IL8(up), s-Ifngg(up), s- 0.84 (0.17) MCP1(up),s-sTNFA(down) OCR no 1 s-CEA(up), s-dDimer(up), s-IL4(down), s-IL10(up),s- 0.85 (0.11) MCP1(down), s-MMPNG(up), s-NSE(down) OCR no 2 s-CEA(up),s-dDimer(up), s-Ifngg(up), s-MCP1(down), s- 0.84 (0.12) MMPNG(up),s-TM(down), s-TPSA(down) OCR no 3 s-CEA(up), s-dDimer(up), s-EGF(down),s-IL6(up), s- 0.84 (0.12) MMPNG(up), s-TM(down) CI no 1 s-FPSA(down),s-IL2(up), s-IL4(down), s-IL6(up), s- 0.84 (0.18) MMPNG(up), s-NGAL(up),s-sTNFR(down) CI no 2 s-CEA(up), s-EGF(down), s-FPSA(down), s-CRP(up),s- 0.84 (0.15) IL4(down), s-IL6(up), s-MMPNG(up) CI no 3 s-dDimer(up),s-IL1b(up), s-IL4(down), s-IL8(up), s- 0.84 (0.14) MCP1(down),s-NGAL(up), s-TM(down) alcohol no 1 s-CEA(up), s-CRP(up), s-IL4(down),s-IL6(up), s-IL10(up), s- 0.84 (0.18) sTNFR(down), s-TPSA(down) alcoholno 2 s-CEA(up), s-dDimer(up), s-EGF(up), s-IL1a(down), s- 0.83 (0.12)IL10(up), s-NSE(up), s-sTNFA(down) alcohol no 3 s-CEA(up), s-dDimer(up),s-IL1a(down), s-IL1b(down), s- 0.83 (0.13) IL4(down), s-TM(up)s-sTNFR(down) AC yes 1 s-FPSA(down), s-IL1b(up), s-IL10(up), s-NGAL(up),s- 0.84 (0.13) TM(down), s-TNFa(up), s-VEGF(down) AC yes 2 s-CEA(up),s-IL1b(up), s-IL4(down), s-NGAL(up), s- 0.8 (0.12) TM(down),s-TPSA(down), s-VEGF(down) AC yes 3 s-FPSA(down), s-IL1b(up),s-IL4(down), s-IL10(up), s- 0.8 (0.22) NGAL(up), s-TM(down),s-VEGF(down) OCR yes 1 s-FPSA(down), s-IL1b(down), s-IL2(down),s-IL4(down), s- 0.84 (0.13) IL8(up), s-MMPNG(up), s-NGAL(up) OCR yes 2s-CEA(up), s-dDimer(up), s-IL8(up), s-IL10(down), s- 0.83 (0.16)Ifngg(down), s-NGAL(up), s-NSE(up) OCR yes 3 s-CEA(up), s-EGF(up),s-CRP(up), s-IL10(down), s- 0.82 (0.15) MCP1(up), s-NGAL(up), s-NSE(up)AC no 1 s-CEA(up), s-IL1a(down), s-IL4(down), s-IL6(up), s-IL8(up), s-0.83 (0.11) TM(up), s-sTNFR(down) AC no 2 s-CEA(up), s-IL1a(down),s-IL1b(up), s-IL4(down), s- 0.82 (0.11) IL8(up), s-MMPNG(up), s-VEGF(up)AC no 3 s-CEA(up), s-IL1a(down), s-IL4(down), s-IL10(up), s- 0.83 (0.1)MMPNG(up), s-TM(up), s-TNFa(up) alcohol yes 1 s-EGF(down), s-CRP(down),s-IL8(up), s-MCP1(up), s- 0.83 (0.12) MMPNG(up), s-NGAL(up),s-sTNFR(down) alcohol yes 2 s-CEA(up), s-EGF(down), s-CRP(down),s-IL1b(up), s- 0.82 (0.11) MMPNG(up), s-NGAL(up), s-TM(up) alcohol yes 3s-CEA(up), s-dDimer(up), s-IL1a(down), s-IL2(down), s- 0.82 (0.11)IL4(down), s-IL10(up), s-NGAL(up) protein yes 1 s-CEA(up), s-IL1b(down),s-IL2(down), s-IL4(down), s- 0.82 (0.18) IL8(up), s-NSE(up) s-TNFa(up)protein yes 2 s-CEA(up), s-EGF(up), s-IL4(down), s-IL8(up), s-IL10(up),s- 0.82 (0.17) TPSA(down), s-VEGF(down) protein yes 3 s-CEA(up),s-IL1b(down), s-IL2(down), s-IL4(down), s- 0.82 (0.17) IL10(up),s-MMPNG(up), s-TM(up) age > 65 1 s-CEA(up), s-dDimer(up), s-FPSA(down),s-CRP(up), s- 0.81 (0.15) IL10(up), s-NGAL(up), s-TM(up) age > 65 2s-CEA(up), s-dDimer(up), s-CRP(up), s-NGAL(up), s- 0.8 (0.13) NSE(up),s-TM(up), s-TPSA(down) age > 65 3 s-dDimer(up), s-IL1a(down),s-IL8(down), s-Ifngg(down), s- 0.79 (0.12) MMPNG(up), s-NGAL(up),s-TM(up) AH no 1 s-CEA(up), s-dDimer(up), s-EGF(up), s-IL4(down),s-IL8(up), s- 0.8 (0.11) IL10(down), s-NSE(up) AH no 2 s-CEA(up),s-dDimer(up), s-CRP(down), s-IL4(down), s 0.8 (0.13) MCP1(up),s-MMPNG(up), s-TNFa(down) AH no 3 s-CEA(up), s-dDimer(up), s-CRP(down),s-IL4(down), s- 0.8 (0.18) IL6(up), s-TM(up), s-TNFa(down) protein no 1s-FPSA(down), s-CRP(up), s-IL2(up), s-IL6(up), s- 0.8 (0.12) NGAL(up),s-TNFa(up), s-VEGF(up) protein no 2 s-CEA(up), s-FPSA(down), s-CRP(up),s-IL5(up), s-IL10(up), s- 0.78 (0.13) NGAL(up), s-VEGF(up) protein no 3s-dDimer(up), s-FPSA(down), s-IL1b(up), s-Ifngg(down), s- 0.78 (0.14)MMPNG(up), s-NGAL(up), s-TM(down) AH yes 1 s-CEA(up), s-IL1a(up),s-IL1b(up), s-IL10(up), s-NGAL(up), s- 0.76 (0.22) sTNFA(down),s-TNFA(up) AH yes 2 s-CEA(up), s-IL1a(up), s-NGAL(up), s-NSE(up),s-TM(up), s- 0.75 (0.16) TNFa(up), s-TPSA(down) AH yes 3 s-CEA(up),s-IL1b(up), s-IL4(down), s-IL10(up), s- 0.75 (0.2) MMPNG(up),s-NGAL(up), s-TM(up) smoking yes 1 s-EGF(down), s-CRP(up), s-IL10(up),s-MMPNG(up), s- 0.74 (0.13) NGAL(up), s-TM(up), s-VEGF(up) smoking yes 2s-CEA(up), s-CRP(up), s-IL10(up), s-MMPNG(up), s- 0.72 (0.14) NGAL(up),s-TM(up), s-TNFa(up) smoking yes 3 s-CEA(up), s-dDimer(up), s-IL2(down),s-IL8(up), s- 0.71 (0.16) IL10(up), s-Ifngg(down), s-NSE(up) CI yes 1s-CEA(up), s-CRP(up), s-IL1b(up), s-IL2(down), s-TM(up), s- 0.74 (0.16)sTNFR(down), s-TPSA(up) CI yes 2 s-CRP(up), s-IL1b(up), s-IL2(down),s-IL6(down), s- 0.74 (0.16) MMPNG(up), s-NGAL(up), s-TNFa(down) CI yes 3s-CRP(up), s-IL1b(up), s-IL2(down), s-MPNG(up), s- 0.74 (0.14) NGAL(up),s-NSE(up), s-TNFa(down)

TABLE 18 Plasma 7 biomarker urothelial cancer (UC) classifiers. Inparenthesis the pattern for up or down regulation of a biomarker in UCare shown. name num Biomarker AUC smoking no 1 p-dDimer(up), p-EGF(up),p-IL1a(up), p-Ifng(up), p-MMPNG(up), p- 0.8 (0.19) TNFa(up),p-VEGF(down) smoking no 2 p-EGF(up), p-IL1a(up), p-IL2(up), p-MMPNG(up),p-NGAL(up), p- 0.79 (0.2) NSE(down), p-TM(up) smoking no 3 p-IL1a(up),p-Ifng(up), p-MMPNG(up), p-NGAL(up), p-NSE(down), p- 0.78 (0.18) TM(up),p-TNFa(up) OCR yes 1 p-IL1b(down), p-IL8(up), p-Ifng(up), p-MCP1(up),p-MMPNG(up), p- 0.79 (0.16) TM(up), p-sTNFR(down) OCR yes 2 p-IL1a(up),p-IL4(up), p-IL8(up), p-IL10(up), p-MCP1(up), p- 0.77 (0.18) TM(up),p-sTNFR(down) OCR yes 3 p-IL1a(up), p-IL1b(down), p-IL6(up), p-IL8(up),p-NGAL(up), p- 0.77 (0.13) NSE(up), p-VEGF(up) OCR no 1 p-IL4(down),p-IL6(up), p-IL10(up), p-MMPNG(up), p- 0.78 (0.09) NGAL(down),p-sTNFR(down), p-VEGF(down) OCR no 2 p-dDimer(up), p-CRP(down),p-IL1a(up), p-IL1b(up), p-IL2(up), p- 0.78 (0.13) IL4(down), p-MMPNG(up)OCR no 3 p-dDimer(up), p-CRP(down), p-IL1b(up), p-IL4(down), p-IL6(up),p- 0.78 (0.13) IL10(up), p-MMPNG(up) CI no 1 p-dDimer(up), p-IL1a(down),p-IL8(down), p-MMPNG(up), p- 0.76 (0.16) TM(up), p-TNFa(up),p-VEGF(down) CI no 2 p-dDimer(up), p-CRP(up), p-IL2(up), p-IL6(up),p-IL8(down), p- 0.76 (0.22) MMPNG(up), p-TNFa(up) CI no 3 p-dDimer(up),p-IL1a(down), p-IL1b(up), p-IL8(down), p- 0.76 (0.19) MMPNG(up),p-TM(up), p-VEGF(down) AC yes 1 p-dDimer(down), p-EGF(down), p-IL6(up),p-IL10(up), p-Ifng(up), p- 0.74 (0.19) MCP1(up), p-TNFa(up) AC yes 2p-dDimer(down), p-IL10(up), p-Ifng(up), p-MCP1(up), p- 0.73 (0.2)NGAL(down), p-sTNFR(up), p-VEGF(down) AC yes 3 p-dDImer(down),p-IL6(up), p-IL8(up), p-IL10(up), p-NSE(down), p- 0.72 (0.2) TM(up),p-TNFa(up) age < 65 1 p-CRP(down), p-IL4(down), p-IL6(up), p-IL8(up),p-10(up), p- 0.74 (0.19) MMPNG(up), p-TNFa(up) age < 65 2 p-EGF(up),p-CRP(down), p-IL1b(up), p-IL8(up), p-Ifng(up), p- 0.74 (0.16) NGAL(up),p-sTNFR(down) age < 65 3 p-dDimer(up), p-EGF(up), p-CRP(down),p-IL8(up), p-IL10(up), p- 0.73 (0.16) Ifng(up), p-MMPNG(up) alcohol no 1p-IL1a(down), p-IL2(up), p-IL8(up), p-Ifng(up), p-MMPNG(up), p- 0.74(0.16) sTNFR(down), p-TNFa(up) alcohol no 2 p-IL1a(down), p-IL2(up),p-IL6(up), p-IL10(up), p-MMPNG(up), p- 0.73 (0.17) TNFa(up), p-VEGF(up)alcohol no 3 p-IL1a(down), p-IL4(down), p-IL6(up), p-IL10(up),p-MMPNG(up), p- 0.73 (0.19) NGAL(up), p-VEGF(up) AH no 1 p-EGF(up),p-CRP(down), p-IL1a(up), p-IL8(up), p-MMPNG(up), p- 0.74 (0.13)TNFa(down), p-VEGF(down) AH no 2 p-EGF(up), p-CRP(down), p-IL1b(down),p-IL8(up), p- 0.73 (0.15) MMPNG(up), p-sTNFR(down), p-VEGF(down) AH no 3p-dDimer(up), p-EGF(up), p-IL1b(down), p-IL6(up), p-IL8(up), p- 0.73(0.14) MMPNG(up), p-VEGF(down) AC no 1 p-IL1b(up), p-IL6(up), p-IL8(up),p-MMPNG(up), p-sTNFR(down), p- 0.74 (0.11) TNFa(up), p-VEGF(up) AC no 2p-dDimer(up), p-IL1a(up), p-IL4(down), p-IL8(up), p-NGAL(up), p- 0.73(0.12) TM(up), p-sTNFR(down) AC no 3 p-IL1a(up), p-IL1b(up),p-IL4(down), p-IL6(up), p-IL8(up), p- 0.72 (0.13) MMPNG(up),p-sTNFR(down) protein no 1 p-EGF(up), p-IL1a(up), p-IL2(up),p-IL4(down), p-MCP1(down), p- 0.73 (0.13) p-MMPNG(up), p-NGAL(up)protein no 2 p-dDimer(up), p-EGF(up), p-CRP(up), p-IL8(down), p- 0.71(0.17) MMPNG(up), p-NSE(down), p-VEGF(up) protein no 3 p-dDimer(up),p-EGF(up), p-IL1b(up), p-IL8(down), p-IL10(up), p- 0.71 (0.14)MMPNG(up), p-VEGF(up) protein yes 1 p-IL1a(up), p-IL2(down), p-IL8(up),p-IL10(up), p-Ifng(up), p- 0.71 (0.19) MCP1(up), p-TM(up) protein yes 2p-IL1a(up), p-IL2(down), p-IL8(up), p-Ifng(up), p-MCP1(up), p- 0.69(0.21) MMPNG(up), p-TM(up) protein yes 3 p-EGF(down), p-CRP(down),p-IL1a(up), p-IL4(down), p-IL8(up), p- 0.69 (0.15) Ifng(up), p-TNFa(up)age > 65 1 p-CRP(up), p-IL1a(down), p-IL10(up), p-MMPNG(up), p-TM(up),p- 0.71 (0.13) TNFa(down), p-VEGF(up) age > 65 2 p-IL1a(down),p-IL6(up), p-IL10(up), p-MMPNG(up), p-TM(up), p- 0.7 (0.14) TNFa(down),p-VEGF(up) age > 65 3 p-CRP(up), p-IL1a(down), p-IL4(down), p-IL6(up),p-MMPNG(up), p- 0.69 (0.14) TM(up), p-TNFa(down) alcohol yes 1p-dDimer(up), p-IL1b(up), p-IL4(down), p-MMPNG(up), p- 0.7 (0.16)NGAL(up), p-NSE(down), p-VEGF(down) alcohol yes 2 p-dDimer(up),p-IL1a(down), p-IL2(up), p-MMPNG(up), p- 0.68 (0.12) NSE(down),p-sTNFR(down), p-TNFa(up) alcohol yes 3 p-dDimer(up), p-CRP(down),p-IL1a(down), p-IL4(down), p- 0.67 (0.15) IL10(up), p-NSE(down),p-sTNFR(down) smoking yes 1 p-IL1a(up), p-IL1b(down), p-IL2(down),p-IL4(down), p-IL10(up), p- 0.68 (0.16) MMPNG(up), p-TNFa(up) smokingyes 2 p-dDimer(up), p-IL1a(up), p-IL4(down), p-Ifng(down), p-MCP1(up),p- 0.68 (0.1) MMPNG(up), p-TM(up) smoking yes 3 p-dDimer(up),p-EGF(down), p-IL1a(up), p-IL4(down), p-IL10(up), p- 0.67 (0.14)Ifng(down), p-MMPNG(up) AH yes 1 p-dDimer(down), p-EGF(down), p-CRP(up),p-IL2(up), p-IL10(up), p- 0.64 (0.17) MMPNG(up), p-TM(up) AH yes 2p-CRP(up), p-IL1a(up), p-IL1b(up), p-IL4(down), p-IL6(up), p- 0.62(0.12) Ifng(up), p-sTNFR(down) AH yes 3 p-EGF(down), p-CRP(up),p-IL4(down), p-IL6(up), p-IL10(up), p- 0.62 (0.14) Ifng(up), p-MMPNG(up)CI yes 1 p-IL1a(up), p-IL8(up), p-IL10(up), p-MCP1(up), p-MMPNG(up), p-0.62 (0.13) NSE(down), p-TM(up) CI yes 2 p-dDimer(up), p-IL2(up),p-IL6(down), p-IL8(up), p-MMPNG(up), p- 0.61 (0.14) TM(up),p-sTNFR(down) CI yes 3 p-IL1a(up), p-IL2(up), p-IL6(down), p-IL8(up),p-MCP1(up), p- 0.61 (0.15) MMPNG(up), p-NSE(down)

The invention is further described with reference to the followingnon-limiting embodiments:

Embodiment 1

A method of identifying a panel of biomarkers for diagnosis of seriousdisease, the method comprising:

-   -   (i) measuring the level of each biomarker in a biomarker panel        in a sample obtained from each subject in a test population;    -   (ii) stratifying the test population into sub-populations        defined by variables that individually divide the test        population into groups containing at least 35% of the total test        population; and    -   (iii) assessing combinations of biomarkers that allow accurate        classification of disease in subjects in the sub-populations of        the test population.

Embodiment 2

The method of embodiment 1, wherein the serious disease is urothelialcancer.

Embodiment 3

The method of embodiment 1 or embodiment 2, wherein the measuredbiomarkers are selected from the group consisting of Bladder TumourAntigen (BTA), Carcino-embryonic antigen (CEA), Human cytokeratin 18(CK18), C-reactive protein (CRP), Creatinine, d Dimer, Epidermal growthfactor (EGF), FAS, Hyaluronidase (HA), IL1α, IL1β, IL2, IL4, IL6, IL8,IL10, Interferon gamma (IFNγ), Monocyte Chemoattractant Protein 1(MCP1), matrix metalloproteinase 9 (MMP9), Neutrophilgelatinase-associated lipocalin (NGAL), MMP9NGAL complex, Neuronspecific enolase (NSE), Free Prostate Specific Antigen (FPSA), TotalProstate Specific Antigen (TPSA), Thrombomodulin (TM), Tumour necrosisfactor α (TNFα), sTNFR1, sTNFR2, Vascular endothelial growth factor(VEGF) and von Willebrand factor (vWF).

Embodiment 4

The method of any one of embodiments 1 to 3, wherein the variables areselected from the group consisting of history of smoking, age, gender,alcohol consumption, history of anti-cholesterol medication, history ofanti-hypertensive medication, occupational exposure to hazardouschemicals, cytological detection of inflammatory cells and presence ofmeasurable dipstick protein in urine.

Embodiment 5

The method of any one of embodiments 1 to 4, wherein the combinations ofbiomarkers are assessed by calculation of the Area Under the Curvemeasurement together with calculation of the standard deviation fromrepeated sub-sampling validation analyses.

Embodiment 6

A method of diagnosing urothelial cancer in a subject, comprising thesteps of:

-   -   (i) assigning the subject to a sub-population according to one        or more factors selected from smoking habits, age, gender,        alcohol consumption, anti-cholesterol medication,        anti-hypertensive medication, occupational risks, exposure to        hazardous chemicals, cytological detection of inflammatory cells        and measurable urinary dipstick protein;    -   (ii) measuring the level of each biomarker of a panel of        biomarkers in one or more samples obtained from the subject; and    -   (iii) correlating the measured levels of the panel of biomarkers        with the likelihood of the subject having urothelial cancer such        that the subject can be classified as having urothelial cancer        or as being a control.

Embodiment 7

A method according to embodiment 6, wherein the subject is a patientpresenting with haematuria.

Embodiment 8

A method according to any one of embodiments 6 or 7, wherein theurothelial cancer is urothelial carcinoma (UC).

Embodiment 9

The method according to any one of embodiments 6 to 8, wherein the oneor more samples are selected from the group consisting of urine, blood,serum and plasma.

Embodiment 10

The method of embodiment 9, wherein the one or more samples includeurine and wherein urinary biomarker levels are volume normalised.

Embodiment 11

The method of any one of embodiments 6 to 10, wherein the subject has ahistory of smoking.

Embodiment 12

The method of embodiment 11, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) urinary EGF, urinary IL6, urinary VEGF and urinary CK18;    -   (ii) urinary EGF, serum IL8, urinary vWF and urinary FAS; and    -   (iii) urinary EGF, urinary IL1α, plasma MMP9NGAL and urinary vWF

Embodiment 13

The method of embodiment 11, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, IL1β, sTNFR, VEGF and CK18;    -   (ii) BTA, EGF, IL1β, vWF and FAS;    -   (iii) EGF, IL1β, IL8, TM, and vWF;    -   (iv) dDimer, EGF, IL1β, IL8, VEGF and vWF;    -   (v) EGF, IL1β, NSE, sTNFR2, VEGF and vWF;    -   (vi) EGF, IL2, TM, sTNFR2, VEGF and CK18;    -   (vii) EGF, IL1α, MMP9, MMP9NGAL, NSE, VEGF and vWF;    -   (viii) EGF, IL1β, NGAL, NSE, sTNFR1, VEGF and vWF; and    -   (ix) dDimer, EGF, IL1α, IL8, NSE, vWF and FAS.

Embodiment 14

The method of embodiment 11, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, EGF, IL1α, IL8 and NGAL;    -   (ii) IL1α, IL2, IL8, NGAL and sTNFR1;    -   (iii) IL1α, IL10, NGAL, NSE and TNFα;    -   (iv) d-Dimer, IL2, IL10, MMP9NGAL, NGAL and sTNFR1;    -   (v) EGF, FPSA, IL10, NGAL, TNFα and TPSA;    -   (vi) CEA, IL1α, IL4, IL8, IL10 and NGAL;    -   (vii) EGF, CRP, IL10, MMP9NGAL, NGAL, TM and VEGF;    -   (viii) CEA, CRP, IL10, MMP9NGAL, NGAL, TM and TNFα; and    -   (ix) CEA, d-Dimer, IL2, IL8, IL10, IFNγ and NSE.

Embodiment 15

The method of embodiment 11, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL4, IFNγ, MCP1, MMP9NGAL and TM;    -   (ii) IL1α, IL4, IFNγ, MCP1 and MMP9NGAL;    -   (iii) EGF, IL1α, IL4, MCP1, MMP9NGAL;    -   (iv) dDimer, IL1α, IL4, IL10, MMP9NGAL and sTNFR1;    -   (v) IL4, IL10, MMP9NGAL, TM, sTNFR1 and TNFα;    -   (vi) IL1β, IL4, IL8, MCP1, MMP9NGAL and TNFα;    -   (vii) IL1α, IL1β, IL2, IL4, IL10, MMP9NGAL and TNFα    -   (viii) d-Dimer, IL1α, IL4, IFNγ, MCP1, MMP9NGAL and TM; and    -   (ix) d-Dimer, EGF, IL1α, IL4, IL10, IFNγ, and MMP9NGAL.

Embodiment 16

The method of any one of embodiments 6 to 10, wherein the subject doesnot have a history of smoking.

Embodiment 17

The method of embodiment 16, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, urinary EGF, plasma IL8 and urinary CK18;    -   (ii) serum CEA, plasma IL8, serum NGAL and serum TM; and    -   (iii) serum CEA, plasma IL8, serum NGAL and plasma NSE.

Embodiment 18

The method of embodiment 16, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, MMP9NGAL, TM, sTNFR2 and VEGF;    -   (ii) BTA, IL4, MMP9, NSE and FAS;    -   (iii) BTA, MMP9NGAL, TNFα, sTNFR2 and VEGF;    -   (iv) BTA, MCP1, MMP9, sTNFR2, vWF and FAS;    -   (v) d-Dimer, IL6, IL8, NGAL, NSE and TNFα;    -   (vi) BTA, IL6, MCP1, TNFα, sTNFR2 and FAS;    -   (vii) EGF, CRP, IL8, NGAL, NSE, TM and HA;    -   (viii) BTA, EGF, IL8, MCP1, NGAL, NSE, sTNFR1; and    -   (ix) BTA, IL4, MCP1, TM, sTNFR2, vWF and FAS.

Embodiment 19

The method of embodiment 16, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, EGF, IL4, NGAL and TNFα;    -   (ii) CEA, EGF, IL8, NGAL and TPSA;    -   (iii) CEA, IL8, MCP1, NGAL and TPSA;    -   (iv) CEA, IL6, IL8, MMP9NGAL, NGAL and VEGF;    -   (v) CEA, d-Dimer, CRP, MMP9NGAL, NGAL and NSE;    -   (vi) CEA, CRP, IL2, MMP9NGAL, NGAL and TM;    -   (vii) CEA, EGF, CRP, IL4, IL8, NGAL and NSE;    -   (viii) CEA, IL6, IL8, IFNγ, NGAL, TM and VEGF;    -   (ix) CEA, FPSA, CRP, IL4, MMP9NGAL, NGAL and TM.

Embodiment 20

The method of embodiment 16, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, MMP9NGAL, NSE, sTNFR1 and VEGF;    -   (ii) IFNγ, MCP1, MMP9NGAL, NGAL and NSE;    -   (iii) IFNγ, MMP9NGAL, NGAL, NSE and TNFα;    -   (iv) IL6, IFNγ, MMP9NGAL, NGAL, NSE and TNFα;    -   (v) d-Dimer, IL1α, IL4, MMP9NGAL, NSE and VEGF;    -   (vi) d-Dimer, EGF, IL1α, IL8, MMP9NGAL and NSE;    -   (vii) d-Dimer, EGF, IL1α, IFNγ, MMP9NGAL, TNFα and VEGF;    -   (viii) EGF, IL1α, IL2, MMP9NGAL, NGAL, NSE and TM; and    -   (ix) IL1α, IFNγ, MMP9NGAL, NGAL, NSE, TM and TNFα.

Embodiment 21

The method of any one of embodiments 6 to 10, wherein the subject isaged 65 years or older.

Embodiment 22

The method of embodiment 21, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum IL2, serum MMP9NGAL, serum NGAL and plasma sTNFR1;    -   (ii) urinary MMP9NGAL, serum NGAL, plasma NGAL and urinary vWF;        and    -   (iii) serum CEA, serum d-Dimer, plasma d-Dimer and serum IFN-γ.

Embodiment 23

The method of embodiment 21, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, IL1β, VEGF, vWF and HA;    -   (ii) d-Dimer, IL1α, NSE, vWF and HA;    -   (iii) BTA, d-Dimer, IL1β, vWF and HA;    -   (iv) BTA, IL1β, IL4, VEGF, vWF and HA;    -   (v) BTA, IL1β, IL8, sTNFR2, vWF and HA;    -   (vi) BTA, EGF, IL1α, NSE, vWF and HA;    -   (vii) d-Dimer, CRP, IL1α, IL2, NSE, vWF and HA;    -   (viii) BTA, IL1α, IL8, MMP9NGAL, vWF, HA and CK18; and    -   (ix) d-Dimer, IL1α, MCP1, NSE, TNFα, vWF and HA.

Embodiment 24

The method of embodiment 21, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, d-Dimer, IL4, NGAL and TM;    -   (ii) IL1α, MMP9NGAL, NGAL, sTNFR1 and TNFα;    -   (iii) IL2, MMP9NGAL, NGAL, sTNFR1 and VEGF;    -   (iv) CEA, d-Dimer, IL1α, NGAL, NSE and TM;    -   (v) CEA, EGF, IL1α, MMP9NGAL, NGAL and TPSA;    -   (vi) CEA, d-Dimer, CRP, IL1β, NGAL and TM;    -   (vii) CEA, d-Dimer, FPSA, CRP, IL10, NGAL and TM;    -   (viii) CEA, d-Dimer, CRP, NGAL, NSE, TM and TPSA; and    -   (ix) d-Dimer, IL1α, IL8, IFNγ, MMP9NGAL, NGAL and TM.

Embodiment 25

The method of embodiment 21, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, IL1α, MMP9NGAL, TM and VEGF;    -   (ii) CRP, IL1α, IL1β, MMP9NGAL and NGAL;    -   (iii) CRP, IL1α, IL4, MMP9NGAL and TM;    -   (iv) CRP, IL1α, IL2, IL4, MMP9NGAL and TM;    -   (v) EGF, CRP, IL1α, IL1β, MMP9NGAL and VEGF;    -   (vi) EGF, IL1α, IL6, MMP9NGAL, TM and TNFα;    -   (vii) CRP, IL1α, IL10, MMP9NGAL, TM, TNFα and VEGF;    -   (viii) IL1α, IL6, IL10, MMP9NGAL, TM, TNFα and VEGF; and    -   (ix) CRP, IL1α, IL4, IL6, MMP9NGAL, TM and TNFα.

Embodiment 26

The method of any one of embodiments 6 to 10, wherein the subject isaged less than 65 years old.

Embodiment 27

The method of embodiment 26, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, urinary EGF, serum IL1α and urinary VEGF;    -   (ii) serum CEA, urinary CRP, serum IL1α and urinary VEGF; and    -   (iii) serum CEA, serum-IL1α, plasma IFNγ and urinary VEGF.

Embodiment 28

The method of embodiment 26, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, IL2, HA, FAS and CK18;    -   (ii) EGF, IL2, MMP9NGAL, HA and CK18;    -   (iii) EGF, vWF, HA, FAS and CK18;    -   (iv) EGF, IL2, IL8, MMP9, HA and CK18;    -   (v) BTA, EGF, IL1β, IL8, HA and CK18;    -   (vi) d-Dimer, EGF, NSE, vWF, HA and CK18;    -   (vii) EGF, CRP, IL1β, IL2, IL8, HA and CK18;    -   (viii) EGF, IL1β, IL4, IL8, vWF, HA and CK18; and    -   (ix) EGF, IL1β, IL6, IL8, MMP9, HA and CK18.

Embodiment 29

The method of embodiment 26, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, IL1α, IL4, TM and TNFα;    -   (ii) CEA, IL1α, IL2, IL4 and IL8;    -   (iii) CEA, IL1α, IL1β, IL4 and VEGF;    -   (iv) CEA, IL1α, IL4, IL8, MMP9NGAL and sTNFR1;    -   (v) CEA, IL1α, IL2, IL4, NSE and sTNFR1;    -   (vi) CEA, EGF, IL1α, IL4, IL8 and TM;    -   (vii) CEA, IL1α, IL2, IL4, IL8, IFNγ and MMP9NGAL;    -   (viii) CEA, EGF, FPSA, IL1α, IL4, IL8 and VEGF; and    -   (ix) CEA, IL1α, IL2, IL8, IFNγ, MCP1 and sTNFR1.

Embodiment 30

The method of embodiment 26, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, IL8, IL10, NSE and VEGF;    -   (ii) d-Dimer, IL8, MMP9NGAL, TNFα and VEGF;    -   (iii) EGF, IL8, IL10, MMP9NGAL and sTNFR1;    -   (iv) EGF, CRP, IL6, IL8, IL10 and sTNFR1;    -   (v) CRP, IL6, IL8, IL10, IFNγ and sTNFR1;    -   (vi) d-Dimer, IL4, IL8, MMP9NGAL, NGAL and TNFα;    -   (vii) CRP, IL4, IL6, IL8, IL10, MMP9NGAL and TNFα;    -   (viii) EGF, CRP, IL1β, IL8, IFNγ, NGAL and sTNFR1; and    -   (ix) d-Dimer, EGF, CRP, IL8, IL10, IFNγ and MMP9NGAL.

Embodiment 31

The method of any one of embodiments 6 to 10, wherein the subject has ahistory of anti-hypertensive medication.

Embodiment 32

The method of embodiment 31, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) urinary EGF, urinary IL1α, serum IL10 and urinary vWF;    -   (ii) urinary EGF, plasma IL10, urinary VEGF and urinary vWF; and    -   (iii) serum sTNFR1, plasma sTNFR1, serum TNFα and urinary vWF.

Embodiment 33

The method of embodiment 31, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, IL2, IL8, sTNFR2 and vWF;    -   (ii) EGF, IL8, NSE, TNFα and vWF;    -   (iii) BTA, EGF, IL4, vWF and HA;    -   (iv) BTA, EGF, IL1β, IL8, VEGF and vWF;    -   (v) d-Dimer, CRP, IL8, sTNFR2, vWF and CK18;    -   (vi) d-Dimer, EGF, IL2, VEGF, vWF and FAS;    -   (vii) CRP, IL1β, IL6, IL8, MMP9, NGAL and vWF;    -   (viii) d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 and vWF; and    -   (ix) BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF.

Embodiment 34

The method of embodiment 31, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, NGAL, NSE, TNFα and TPSA;    -   (ii) CEA, MMP9NGAL, NGAL, TM and TNFα;    -   (iii) CEA, IL1β, NGAL, sTNFR1 and TPSA;    -   (iv) CEA, IL1β, IL10, NGAL, TM and VEGF;    -   (v) CEA, d-Dimer, IL1β, MMP9NGAL, NGAL and TM;    -   (vi) CEA, EGF, IL1α, IL1β, NGAL and TNFα;    -   (vii) CEA, IL1α, IL1β, IL10, NGAL, sTNFR1 and TNFα;    -   (viii) CEA, IL1α, NGAL, NSE, TM, TNFα and TPSA; and    -   (ix) CEA, IL1β, IL4, IL10, MMP9NGAL, NGAL and TM.

Embodiment 35

The method of embodiment 31, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, IL1β, IL4, IFNγ and VEGF;    -   (ii) EGF, CRP, IL2, IL4 and IL8;    -   (iii) EGF, CRP, IL2, IL10 and NGAL;    -   (iv) EGF, IL6, IL10, IFNγ, MCP1 and MMP9NGAL;    -   (v) d-Dimer, EGF, IL1β, IL4, IL6 and MCP1;    -   (vi) EGF, CRP, IL1β, IL2, MMP9NGAL and NGAL;    -   (vii) d-Dimer, EGF, CRP, IL2, IL10, MMP9NGAL and TM;    -   (viii) CRP, IL1α, IL1β, IL4, IL6, IFNγ and sTNFR1; and    -   (ix) EGF, CRP, IL4, IL6, IL10, IFNγ and MMP9NGAL.

Embodiment 36

The method of any one of embodiments 6 to 10, wherein the subject has nohistory of anti-hypertensive medication.

Embodiment 37

The method of embodiment 36, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, urinary CRP, urinary NSE and serum TNFα;    -   (ii) serum CEA, urinary CRP, serum IL4 and urinary sTNFR1; and    -   (iii) urinary Creatinine, serum IL6, plasma MMP9NGAL and urinary        VEGF.

Embodiment 38

The method of embodiment 36, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, NGAL, VEGF, HA and CK18;    -   (ii) d-Dimer, TNFα, VEGF, HA and CK18;    -   (iii) MMP9, NSE, TM, VEGF and FAS;    -   (iv) EGF, NGAL, VEGF, vWF, HA and CK18;    -   (v) CRP, IL1β, IL6, sTNFR1, VEGF and vWF;    -   (vi) d-Dimer, EGF, IL4, VEGF, HA and CK18;    -   (vii) CRP, IL1β, IL6, IL8, MMP9, NGAL and vWF;    -   (viii) d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 and vWF; and    -   (ix) BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF.

Embodiment 39

The method of embodiment 36, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, d-Dimer, IL4, MMP9NGAL and sTNFR1;    -   (ii) CEA, EGF, IL10, MMP9NGAL and TNFα;    -   (iii) CEA, d-Dimer, CRP, IL4 and IL10;    -   (iv) CEA, d-Dimer, CRP, IL4, IL10 and TM;    -   (v) CEA, d-Dimer, CRP, IL4, IL6 and MMP9NGAL;    -   (vi) CEA, d-Dimer, IL2, IL4, IL8 and MMP9NGAL;    -   (vii) CEA, d-Dimer, EGF, IL4, IL8, IL10 and NSE;    -   (viii) CEA, d-Dimer, CRP, IL4, MCP1, MMP9NGAL and TNFα; and    -   (ix) CEA, d-Dimer, CRP, IL4, IL6, TM and TNFα.

Embodiment 40

The method of embodiment 36, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, IL1α, IL8, MMP9NGAL and VEGF;    -   (ii) IL1α, IL8, IFNγ, MMP9NGAL and VEGF;    -   (iii) CRP, IL1α, IL8, MMP9NGAL and NGAL;    -   (iv) EGF, CRP, IL1β, IL8, MMP9NGAL and VEGF;    -   (v) CRP, IL1α, IL6, IL8, IL10, MMP9NGAL;    -   (vi) EGF, IL1β, IL4, IL8, MMP9NGAL and VEGF;    -   (vii) EGF, CRP, IL1α, IL8, MMP9NGAL, TNFα and VEGF;    -   (viii) EGF, CRP, IL1β, IL8, MMP9NGAL, sTNFR1 and VEGF; and    -   (ix) d-Dimer, EGF, IL1β, IL6, IL8, MMP9NGAL and VEGF.

Embodiment 41

The method of any one of embodiments 6 to 10, wherein the subject hascytological detection of inflammatory cells.

Embodiment 42

The method of embodiment 41, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) urinary BTA, serum CEA, plasma IL10 and urinary CK18;    -   (ii) urinary BTA, plasma IL6, serum NSE and plasma NSE; and    -   (iii) urinary dipstick protein, urinary BTA, plasma IL6 and        serum NGAL.

Embodiment 43

The method of embodiment 41, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, IL1α, NGAL, sTNFR1 and vWF;    -   (ii) BTA, IL8, MMP9NGAL, VEGF and CK18;    -   (iii) BTA, IL6, MMP9NGAL, NSE and CK18;    -   (iv) BTA, IL2, MMP9NGAL, sTNFR1, TNFα and VEGF;    -   (v) BTA, IL2, MMP9NGAL, NGAL, TNFα and CK18;    -   (vi) BTA, IL2, MMP9NGAL, NSE, VEGF and CK18;    -   (vii) BTA, IL2, MMP9NGAL, NGAL, sTNFR1, TNFα and VEGF;    -   (viii) BTA, IL2, MMP9NGAL, TM, sTNFR1, vWF and FAS; and    -   (ix) BTA, IL2, MMP9NGAL, sTNFR1, VEGF, vWF and CK18.

Embodiment 44

The method of embodiment 41, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, IL1α, NGAL, NSE and TPSA;    -   (ii) IL1α, MMP9NGAL, NGAL, TPSA and VEGF;    -   (iii) CEA, IL1α, IL10, NGAL and VEGF;    -   (iv) CEA, IL10, MMP9NGAL, NGAL, TNFα and VEGF;    -   (v) IL1α, IL10, MMP9NGAL, NGAL, NSE and VEGF;    -   (vi) CRP, IL10, MMP9NGAL, NGAL, TPSA and VEGF;    -   (vii) CEA, CRP, IL1β, IL2, TM, sTNFR1 and TPSA;    -   (viii) CRP, IL1β, IL2, IL6, MMP9NGAL, NGAL and TNFα; and    -   (ix) CRP, IL1β, IL2, MMP9NGAL, NGAL, NSE and TNFα.

Embodiment 45

The method of embodiment 41, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, IL6, IL8, MMP9NGAL and NSE;    -   (ii) IL6, IFNγ, MMP9NGAL, NSE and sTNFR1;    -   (iii) IL1α, IL1β, IL8, IL10 and MMP9NGAL;    -   (iv) IL6, IL8, IFNγ, MMP9NGAL, NGAL and NSE;    -   (v) IL1α, IL6, MMP9NGAL, NSE, TM and TNFα;    -   (vi) d-Dimer, IL4, IL8, IFNγ, MMP9NGAL and VEGF;    -   (vii) IL1α, IL8, IL10, MCP1, MMP9NGAL, NSE and TM;    -   (viii) d-Dimer, IL2, IL6, IL8, MMP9NGAL, TM and sTNFR1; and    -   (ix) IL1α, IL2, IL6, IL8, MCP1, MMP9NGAL and NSE.

Embodiment 46

The method of any one of embodiments 6 to 10, wherein the subject doesnot have cytological detection of inflammatory cells.

Embodiment 47

The method of embodiment 46, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, plasma IL8, serum TNFα and urinary FAS;    -   (ii) urinary EGF, serum EGF, serum FPSA and serum IL4; and    -   (iii) urinary EGF, urinary CRP, urinary IL4 and urinary NSE.

Embodiment 48

The method of embodiment 46, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, CRP, IL4, TM and vWF;    -   (ii) BTA, d-Dimer, EGF, CRP and IL4;    -   (iii) EGF, CRP, IL4, IL6 and vWF;    -   (iv) d-Dimer, EGF, CRP, IL4, sTNFR1 and vWF;    -   (v) d-Dimer, EGF, CRP, IL4, sTNFR1 and sTNFR2;    -   (vi) EGF, IL2, IL4, sTNFR2, VEGF and vWF;    -   (vii) EGF, CRP, IL4, MCP1, VEGF, FAS and CK18;    -   (viii) d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and vWF; and    -   (ix) d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and CK18.

Embodiment 49

The method of embodiment 46, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, EGF, CRP, IL4 and IFNγ;    -   (ii) d-Dimer, FPSA, IL6, IFNγ and NGAL;    -   (iii) IL1α, IL4, MMP9NGAL, NGAL and TM;    -   (iv) IL4, MMP9NGAL, NGAL, NSE, sTNFR1 and TPSA;    -   (v) CEA, EGF, FPSA, IL4, NSE and sTNFR1;    -   (vi) CEA, EGF, FPSA, IL4, MCP1 and VEGF;    -   (vii) FPSA, IL2, IL4, IL6, MMP9NGAL, NGAL and sTNFR1;    -   (viii) CEA, EGF, FPSA, CRP, IL4, IL6 and MMP9NGAL; and    -   (ix) d-Dimer, IL1β, IL4, IL8, MCP1, NGAL and TM.

Embodiment 50

The method of embodiment 46, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, IL1β, IL8, MMP9NGAL and TM;    -   (ii) d-Dimer, IL8, TM, TNFα and VEGF;    -   (iii) IL2, IL8, MMP9NGAL, TM and TNFα;    -   (iv) d-Dimer, IL8, MMP9NGAL, NSE, TM and TNFα;    -   (v) d-Dimer, IL2, IL8, MMP9NGAL, NSE and TNFα;    -   (vi) d-Dimer, IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (vii) d-Dimer, IL1α, IL8, MMP9NGAL, TM, TNFα and VEGF;    -   (viii) d-Dimer, CRP, IL2, IL6, IL8, MMP9NGAL and TNFα; and    -   (ix) d-Dimer, IL1α, IL1β, IL8, MMP9NGAL, TM and VEGF.

Embodiment 51

The method of any one of embodiments 6 to 10, wherein the subject has ahistory of alcohol consumption.

Embodiment 52

The method of embodiment 51, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) urinary EGF, urinary IL1β, serum MMP9NGAL and urinary vWF;    -   (ii) serum CEA, urinary EGF, urinary vWF and urinary CK18; and    -   (iii) serum CEA, urinary EGF, plasma NSE and urinary vWF.

Embodiment 53

The method of embodiment 51, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, MMP9, sTNFR2, VEGF and vWF;    -   (ii) EGF, IL1α, IL4, vWF and FAS;    -   (iii) EGF, IL1α, MMP9, vWF and HA;    -   (iv) d-Dimer, EGF, CRP, IL1α, IL6 and vWF;    -   (v) EGF, CRP, IL1α, sTNFR, vWF and CK18;    -   (vi) BTA, EGF, CRP, IL1α, vWF and FAS;    -   (vii) EGF, IL1α, IL6, NGAL, sTNFR2, vWF and FAS;    -   (viii) EGF, IL1α, IL2, IL6, NGAL, VEGF and vWF; and    -   (ix) EGF, IL1α, NGAL, NSE, sTNFR2, vWF and CK18.

Embodiment 54

The method of embodiment 51, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, IL1β, IL6, IL8 and NGAL;    -   (ii) d-Dimer, IL1β, IL4, IFNγ and NGAL;    -   (iii) CRP, IL1β, IL4, MCP1 and NGAL;    -   (iv) EGF, CRP, IL1α, IL1β, NGAL and TPSA;    -   (v) CEA, CRP, IL1β, IL2, NGAL and NSE;    -   (vi) CEA, d-Dimer, CRP, IL1α, IL6 and NGAL;    -   (vii) EGF, CRP, IL8, MCP1, MMP9NGAL, NGAL and sTNFR1;    -   (viii) CEA, EGF, CRP, IL1β, MMP9NGAL, NGAL and TM; and    -   (ix) CEA, d-Dimer, IL1α, IL2, IL4, IL10 and NGAL.

Embodiment 55

The method of embodiment 51, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, IL4, MMP9NGAL, NSE and TM;    -   (ii) IL1β, IL4, MMP9NGAL, NSE and TNFα;    -   (iii) EGF, CRP, IL4, MMP9NGAL and sTNFR1;    -   (iv) IL1α, IL2, IL4, MMP9NGAL, NSE and TNFα;    -   (v) IL2, IL4, IL6, MMP9NGAL, NSE and TM;    -   (vi) CRP, IL1α, IL1β, IL4, MMP9NGAL and TNFα;    -   (vii) d-Dimer, IL1β, IL4, MMP9NGAL, NGAL, NSE and VEGF;    -   (viii) d-Dimer, IL1α, IL2, MMP9NGAL, NSE, sTNFR and TNFα; and    -   (ix) d-Dimer, CRP, IL1α, IL4, IL10, NSE and sTNFR.

Embodiment 56

The method of any one of embodiments 6 to 10, wherein the subject doesnot have a history of alcohol consumption.

Embodiment 57

The method of embodiment 56, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum MMP9NGAL, serum sTNFR1, serum TNFα and urinary VEGF;    -   (ii) serum CEA, urinary EGF, serum IL10 and serum NGAL; and    -   (iii) urinary IL6, plasma MMP9NGAL, urinary VEGF and urinary        CK18.

Embodiment 58

The method of embodiment 56, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) IL2, IL8, NGAL, HA and CK18;    -   (ii) IL2, IL4, VEGF, HA and CK18;    -   (iii) IL1β, IL2, IL8, NGAL and CK18;    -   (iv) IL2, IL4, IL8, NGAL, HA and CK18;    -   (v) BTA, d-Dimer, IL2, IL8, MMP9NGAL and CK18;    -   (vi) IL2, IL4, IL8, sTNFR2, HA and CK18;    -   (vii) IL1β, IL2, IL6, IL8, NGAL, NSE and CK18;    -   (viii) IL1α, IL2, IL6, IL8, NGAL, HA and CK18; and    -   (ix) BTA, IL1α, IL2, IL8, NGAL, VEGF and CK18.

Embodiment 59

The method of embodiment 56, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, IL1α, IL8, TM and sTNFR1;    -   (ii) CEA, IL1α, IL6, NGAL and TM;    -   (iii) CEA, IL1α, IL2, TM and sTNFR1;    -   (iv) CEA, IL2, IL8, NSE, TM and sTNFR1;    -   (v) CEA, IL10, MMP9NGAL, NSE, TM and sTNFR1;    -   (vi) CEA, CRP, IL2, IL10, NGAL and TM;    -   (vii) CEA, CRP, IL4, IL6, IL10, sTNFR1 and TPSA;    -   (viii) CEA, d-Dimer, EGF, IL1α, IL10, NSE and sTNFR1; and    -   (ix) CEA, d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1.

Embodiment 60

The method of embodiment 56, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (ii) EGF, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (iii) IL1α, IL8, IL10, MMP9NGAL and VEGF;    -   (iv) IL1α, IL1β, IL10, IFNγ, MMP9NGAL and VEGF;    -   (v) EGF, CRP, IL1α, MMP9NGAL, TNFα and VEGF;    -   (vi) IL1α, IL6, IL8, IFNγ, MMP9NGAL and sTNFR1;    -   (vii) IL1α, IL2, IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (viii) IL1α, IL2, IL6, IL10, MMP9NGAL, TNFα and VEGF; and    -   (ix) IL1α, IL4, IL6, IL10, MMP9NGAL, NGAL and VEGF.

Embodiment 61

The method of any one of embodiments 6 to 10, wherein the subject has ahistory of exposure to occupational risks or hazardous chemicals.

Embodiment 62

The method of embodiment 61, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, urinary EGF, urinary VEGF and urinary vWF;    -   (ii) urinary EGF, serum IL8, urinary vWF and urinary HA; and    -   (iii) serum IL4, plasma IL8, serum MCP1 and urinary VEGF.

Embodiment 63

The method of embodiment 61, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, IL2, IL4, MMP9NGAL and VEGF;    -   (ii) BTA, IL1α, IL8, NGAL and NSE;    -   (iii) BTA, CRP, IL4, NSE and CK18;    -   (iv) BTA, d-Dimer, CRP, IL4, sTNFR1 and vWF;    -   (v) IL4, IL8, NGAL, NSE, TM and sTNFR1;    -   (vi) CRP, IL2, IL8, MCP1, MMP9NGAL and TNFα;    -   (vii) EGF, IL1α, IL8, MMP9NGAL, NSE, vWF and CK18;    -   (viii) EGF, IL6, IL8, MMP9NGAL, NSE, VEGF and vWF; and    -   (ix) CRP, IL1α, IL6, IL8, MMP9NGAL, NSE and VEGF.

Embodiment 64

The method of embodiment 61, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) IL2, IL10, NGAL, NSE and VEGF;    -   (ii) CEA, IL4, IL8, NGAL and TM;    -   (iii) CEA, CRP, NGAL, NSE and sTNFR1;    -   (iv) d-Dimer, CRP, IL6, IL8, NSE and sTNFR1;    -   (v) CEA, IL4, IL10, IFNγ, MCP1 and NGAL;    -   (vi) FPSA, IL4, IL8, MMP9NGAL, NSE and sTNFR1;    -   (vii) FPSA, IL1β, IL2, IL4, IL8, MMP9NGAL and NGAL;    -   (viii) CEA, d-Dimer, IL8, IL10, IFNγ, NGAL and NSE; and    -   (ix) CEA, EGF, CRP, IL10, MCP1, NGAL and NSE.

Embodiment 65

The method of embodiment 61, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, IL6, MMP9NGAL, TM and sTNFR1;    -   (ii) IL1α, IL1β, IL6, IL8 and TNFα;    -   (iii) IL8, MMP9NGAL, NGAL, NSE and TNFα;    -   (iv) IL1β, IL2, IL8, MMP9NGAL, NGAL and NSE;    -   (v) IL1β, IL8, IL10, MCP1, NGAL and TM;    -   (vi) IL8, IFNγ, MMP9NGAL, TM, sTNFR1 and TNFα;    -   (vii) IL1β, IL8, IFNγ, MCP1, MMP9NGAL, TM and sTNFR1;    -   (viii) IL1α, IL4, IL8, IL10, MCP1, TM and sTNFR1; and    -   (ix) IL1α, IL1β, IL6, IL8, NGAL, NSE and VEGF.

Embodiment 66

The method of any one of embodiments 6 to 10, wherein the subject doesnot have a history of exposure to occupational risks or hazardouschemicals.

Embodiment 67

The method of embodiment 66, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, serum d-Dimer, urinary EGF and serum IL1α;    -   (ii) serum CEA, serum d-Dimer, serum IL6 and serum MCP1; and    -   (iii) urinary BTA, serum CEA, urinary TNFα and urinary CK18.

Embodiment 68

The method of embodiment 66, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, TM, TNFα, sTNFR2 and vWF;    -   (ii) BTA, TM, TNFα, vWF and FAS;    -   (iii) EGF, NSE, TNFα, vWF and HA;    -   (iv) IL6, MCP1, TNFα, vWF, FAS and CK18;    -   (v) BTA, d-Dimer, CRP, TNFα, vWF and HA;    -   (vi) BTA, IL1α, TNFα, vWF, HA and FAS;    -   (vii) BTA, d-Dimer, MMP9NGAL, TM, TNFα, vWF and HA;    -   (viii) IL6, NGAL, sTNFR, TNFα, vWF, FAS and CK18; and    -   (ix) BTA, IL1α, IL1β, IL6, NGAL, TNFα and CK18.

Embodiment 69

The method of embodiment 66, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, d-Dimer, NSE, TM and TPSA;    -   (ii) CEA, EGF, IL10, MCP1 and sTNFR1;    -   (iii) CEA, d-Dimer, CRP, MCP1 and NGAL;    -   (iv) CEA, d-Dimer, EGF, IL8, IL10 and TM;    -   (v) CEA, d-Dimer, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (vi) CEA, d-Dimer, EGF, IL6, NGAL and TM;    -   (vii) CEA, d-Dimer, IL4, IL10, MCP1, MMP9NGAL and NSE;    -   (viii) CEA, d-Dimer, IFNγ, MCP1, MMP9NGAL, TM and TPSA; and    -   (ix) CEA, d-Dimer, EGF, IL6, IL10, MMP9NGAL and TM.

Embodiment 70

The method of embodiment 66, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL4, IL6, IFNγ, MMP9NGAL and NGAL;    -   (ii) IL1β, IL4, IL10, MMP9NGAL and TM;    -   (iii) IL2, IL4, IL6, IFNγ and MMP9NGAL;    -   (iv) IL2, IL4, IL10, MMP9NGAL, TNFα and VEGF;    -   (v) CRP, IL4, IL10, MMP9NGAL, TNFα and VEGF;    -   (vi) IL1α, IL4, IL10, IFNγ, MMP9NGAL and NSE;    -   (vii) IL4, IL6, IL10, MMP9NGAL, NGAL, sTNFR1 and VEGF;    -   (viii) d-Dimer, CRP, IL1α, IL1β, IL2, IL4 and MMP9NGAL; and    -   (ix) d-Dimer, CRP, IL1β, IL4, IL6, IL10 and MMP9NGAL.

Embodiment 71

The method of any one of embodiments 6 to 10, wherein the subject has ahistory of anti-cholesterol medication.

Embodiment 72

The method of embodiment 71, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum MCP1, plasma MCP1, serum NGAL and plasma NGAL;    -   (ii) urinary CRP, serum IL2, serum NGAL and plasma NGAL; and    -   (iii) urinary Creatinine, serum NGAL, plasma NGAL and plasma        VEGF.

Embodiment 73

The method of embodiment 71, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, MCP1, sTNFR2, vWF and FAS;    -   (ii) d-Dimer, IL6, MMP9NGAL, NSE and VEGF;    -   (iii) BTA, MCP1, sTNFR2, vWF and FAS;    -   (iv) d-Dimer, IL6, NGAL, NSE, VEGF and HA;    -   (v) IL1β, IL6, IL8, MMP9NGAL, NSE and VEGF;    -   (vi) BTA, d-Dimer, IL6, NGAL, NSE and VEGF;    -   (vii) BTA, CRP, IL1β, IL8, sTNFR2, vWF and FAS;    -   (viii) d-Dimer, IL4, IL6, MMP9, NSE, VEGF and CK18; and    -   (ix) BTA, CRP, IL1α, IL2, sTNFR2, vWF and FAS.

Embodiment 74

The method of embodiment 71, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) IL6, IL8, NGAL, TPSA and VEGF;    -   (ii) FPSA, NGAL, TM, TNFα and VEGF;    -   (iii) IL1β, IL2, NGAL, TM and VEGF;    -   (iv) IL1α, MCP1, MMP9NGAL, NGAL, TM and TNFα;    -   (v) CEA, FPSA, IL8, NGAL, TM and VEGF;    -   (vi) FPSA, IL4, NGAL, NSE, TNFα and VEGF;    -   (vii) FPSA, IL1β, IL10, NGAL, TM, TNFα and VEGF;    -   (viii) CEA, IL1β, IL4, NGAL, TM, TPSA and VEGF; and    -   (ix) FPSA, IL1β, IL4, IL10, NGAL, TM and VEGF.

Embodiment 75

The method of embodiment 71, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL2, IFNγ, MCP1, MMP9NGAL and TM;    -   (ii) IL1α, IL1β, IL6, TNFα and VEGF;    -   (iii) IL4, IL6, IFNγ, MCP1 and TNFα;    -   (iv) d-Dimer, IL2, IL6, MMP9NGAL, TM and TNFα;    -   (v) IL2, IL10, IFNγ, MCP1, MMP9NGAL and TNFα;    -   (vi) IL6, MCP1, NGAL, NSE, TM and TNFα;    -   (vii) d-Dimer, EGF, IL6, IL10, IFNγ, MCP1 and TNFα;    -   (viii) d-Dimer, IL10, IFNγ, MCP1, NGAL, sTNFR and VEGF; and    -   (ix) d-Dimer, IL6, IL8, IL10, NSE, TM and TNFα.

Embodiment 76

The method of any one of embodiments 6 to 10, wherein the subject doesnot have a history of anti-cholesterol medication.

Embodiment 77

The method of embodiment 76, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, urinary EGF, urinary HA and urinary CK18;    -   (ii) serum CEA, urinary EGF, urinary IL8 and urinary CK18; and    -   (iii) serum CEA, urinary EGF, plasma IL6 and urinary MMP9NGAL.

Embodiment 78

The method of embodiment 76, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) BTA, CRP, IL2, IL4 and CK18;    -   (ii) EGF, IL1β, NGAL, VEGF and CK18;    -   (iii) BTA, IL4, IL8, HA and CK18;    -   (iv) EGF, CRP, IL4, VEGF, HA and CK18;    -   (v) EGF, IL4, IL6, IL8, vWF and CK18;    -   (vi) BTA, EGF, IL4, IL8, HA and CK18;    -   (vii) BTA, EGF, CRP, IL4, sTNFR1, HA and CK18;    -   (viii) EGF, IL1α, IL1β, IL4, sTNFR1, VEGF and CK18; and    -   (ix) EGF, CRP, IL4, MMP9NGAL, NGAL, HA and CK18.

Embodiment 79

The method of embodiment 76, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, FPSA, IL10, IFNγ and NGAL;    -   (ii) CEA, IL1α, IL1β, MMP9NGAL and sTNFR1;    -   (iii) CEA, IL1α, MMP9NGAL, TM and TNFα;    -   (iv) CEA, IL1α, IL1β, IL6, NGAL and NSE;    -   (v) CEA, IL4, IL6, IL8, MMP9NGAL and TNFα;    -   (vi) CEA, d-Dimer, IL1α, IL4, IL6 and sTNFR1;    -   (vii) CEA, IL1α, IL4, IL6, IL8, TM and sTNFR1;    -   (viii) CEA, IL1α, IL1β, IL4, IL8, MMP9NGAL and VEGF; and    -   (ix) CEA, IL1α, IL4, IL10, MMP9NGAL, TM and TNFα.

Embodiment 80

The method of embodiment 76, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) IL1α, IL8, MMP9NGAL, NGAL and sTNFR1;    -   (ii) IL1α, IL1β, IL4, IFNγ and sTNFR1;    -   (iii) IL1α, IL1β, IL8, TM and sTNFR1;    -   (iv) d-Dimer, IL1α, IL4, IL10, MMP9NGAL and TNFα;    -   (v) CRP, IL8, IL10, MMP9NGAL, TM and sTNFR1;    -   (vi) d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1;    -   (vii) IL1β, IL6, IL8, MMP9NGAL, sTNFR1, TNFα and VEGF;    -   (viii) d-Dimer, IL1α, IL4, IL8, NGAL, TM and sTNFR1; and    -   (ix) IL1α, IL1β, IL4, IL6, IL8, MMP9NGAL and sTNFR1.

Embodiment 81

The method of any one of embodiments 6 to 10, wherein the subject hasproteinuria.

Embodiment 82

The method of embodiment 81, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) serum CEA, plasma CRP, urinary IL8 and plasma TNFα;    -   (ii) urinary EGF, urinary IL1β, serum IL6 and urinary vWF; and    -   (iii) serum CEA, plasma SERUM-IL1α, urinary NSE and serum NSE.

Embodiment 83

The method of embodiment 81, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) EGF, IL2, NSE, TM and CK18;    -   (ii) EGF, IL6, sTNFR1, HA and CK18;    -   (iii) EGF, NGAL, vWF, HA and CK18;    -   (iv) EGF, IL8, sTNFR2, VEGF, vWF and HA;    -   (v) EGF, IL1α, MMP9, NSE, vWF and HA;    -   (vi) EGF, CRP, IL2, IL4, TM and CK18;    -   (vii) EGF, IL1β, IL2, NSE, TM, VEGF and vWF;    -   (viii) EGF, IL1β, MMP9, MMP9NGAL, TNFα, vWF and HA; and    -   (ix) EGF, IL2, IL4, NGAL, NSE, TM and CK18.

Embodiment 84

The method of embodiment 81, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) CEA, IL8, IL10, NSE and TNFα;    -   (ii) CEA, IL2, IL8, MMP9NGAL and NSE;    -   (iii) CEA, IL2, IL6, IL10 and NSE;    -   (iv) CEA, IL1β, IL2, IL8, IL10 and NSE;    -   (v) CEA, IL1β, IL2, IL8, NSE and TPSA;    -   (vi) CEA, CRP, IL10, MMP9NGAL, NGAL and VEGF;    -   (vii) CEA, IL1β, IL2, IL4, IL8, NSE and TNFα;    -   (viii) CEA, EGF, IL4, IL8, IL10, TPSA and VEGF; and    -   (ix) CEA, IL1β, IL2, IL4, IL10, MMP9NGAL and TM.

Embodiment 85

The method of embodiment 81, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) CRP, IL1α, IL8, IFNγ, TM;    -   (ii) CRP, IL1α, IL8, IFNγ, NGAL;    -   (iii) IL1α, IL2, IL8, MCP1, TM;    -   (iv) EGF, IL1α, IL4, IL8, IFNγ, TM;    -   (v) d-Dimer, IL1α, IL8, IFNγ, MCP1, TM;    -   (vi) IL1α, IL8, IFNγ, MCP1, TM, TNFα;    -   (vii) IL1α, IL2, IL8, IL10, IFNγ, MCP1, TM;    -   (viii) IL1α, IL2, IL8, IFNγ, MCP1, MMP9NGAL, TM; and    -   (ix) EGF, CRP, IL1α, IL4, IL8, IFNγ, TNFα.

Embodiment 86

The method of any one of embodiments 6 to 10, wherein the subject doesnot have proteinuria.

Embodiment 87

The method of embodiment 86, wherein the panel of biomarkers is selectedfrom the group consisting of:

-   -   (i) urinary BTA, urinary NGAL, serum NGAL and urinary TNFα;    -   (ii) urinary d-Dimer, urinary CRP, urinary NGAL and serum TNFα;        and    -   (iii) serum CEA, urinary CRP, plasma MMP9NGAL and urinary NGAL.

Embodiment 88

The method of embodiment 86, wherein the one or more sample is urine andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, CRP, IL4, NGAL and sTNFR2;    -   (ii) CRP, MMP9NGAL, NGAL, sTNFR2 and VEGF;    -   (iii) BTA, CRP, IL4, NGAL and sTNFR2;    -   (iv) CRP, MCP1, MMP9, NGAL, sTNFR2 and VEGF;    -   (v) d-Dimer, CRP, IL2, IL4, NGAL and sTNFR;    -   (vi) BTA, CRP, IL2, NGAL, sTNFR2 and vWF;    -   (vii) d-Dimer, CRP, IL1α, IL4, MMP9NGAL, TM and CK18;    -   (viii) BTA, EGF, CRP, MMP9, NGAL, vWF and FAS; and    -   (ix) BTA, CRP, NGAL, NSE, TM, sTNFR2 and vWF.

Embodiment 89

The method of embodiment 86, wherein the one or more sample is serum andthe panel of biomarkers is selected from the group consisting of:

-   -   (i) FPSA, IL1α, IL4, IFNγ and NGAL;    -   (ii) d-Dimer, IL2, IL4, NGAL and TM;    -   (iii) d-Dimer, IL6, NGAL, TM and sTNFR1;    -   (iv) d-Dimer, IL1β, IL8, NGAL, TM and TNFα;    -   (v) CEA, IL4, IL8, NGAL, TNFα and TPSA;    -   (vi) d-Dimer, FPSA, IL2, IL6, IL8 and NGAL;    -   (vii) FPSA, CRP, IL2, IL6, NGAL, TNFα and VEGF;    -   (viii) CEA, FPSA, CRP, IL6, IL10, NGAL and VEGF; and    -   (ix) d-Dimer, FPSA, IL1β, IFNγ, MMP9NGAL, NGAL and TM.

Embodiment 90

The method of embodiment 86, wherein the one or more sample is plasmaand the panel of biomarkers is selected from the group consisting of:

-   -   (i) d-Dimer, IL4, MCP1, MMP9NGAL and TNFα;    -   (ii) EGF, IL1α, IL2, MMP9NGAL and NGAL;    -   (iii) d-Dimer, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (iv) d-Dimer, IL1β, IL4, IL8, IL10 and MMP9NGAL;    -   (v) d-Dimer, EGF, IL8, IL10, MMP9NGAL and TM;    -   (vi) d-Dimer, EGF, IFNγ, MMP9NGAL, NSE and VEGF;    -   (vii) EGF, IL1α, IL2, IL4, MCP1, MMP9NGAL and NGAL;    -   (viii) d-Dimer, EGF, CRP, IL8, MMP9NGAL, NSE and VEGF; and    -   (ix) d-Dimer, EGF, IL1β, IL8, IL10, MMP9NGAL and VEGF.

Embodiment 91

A solid state device comprising a substrate comprising an antibody toone or more of the biomarkers selected from Bladder Tumour Antigen(BTA), Carcino-embryonic antigen (CEA), Human cytokeratin 18 (CK18),C-reactive protein (CRP), Creatinine, d Dimer, Epidermal growth factor(EGF), FAS, Hyaluronidase (HA), IL1α, IL1β, IL2, IL4, IL6, IL8, IL10,Interferon gamma (IFNγ), Monocyte Chemoattractant Protein 1 (MCP1),matrix metalloproteinase 9 (MMP9), Neutrophil gelatinase-associatedlipocalin (NGAL), MMP9NGAL complex, Neuron specific enolase (NSE), FreeProstate Specific Antigen (FPSA), Total Prostate Specific Antigen(TPSA), Thrombomodulin (TM), Tumour necrosis factor α (TNFα), sTNFR1,sTNFR2, Vascular endothelial growth factor (VEGF) and von Willebrandfactor (vWF).

Embodiment 92

A solid state device according to embodiment 91, wherein the antibody isa monoclonal antibody.

Embodiment 93

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) urinary EGF, urinary IL6, urinary VEGF and urinary CK18;    -   (ii) urinary EGF, serum IL8, urinary vWF and urinary FAS;    -   (iii) urinary EGF, urinary IL1α, plasma MMP9NGAL and urinary        vWF;    -   (iv) EGF, IL1β, sTNFR, VEGF and CK18;    -   (v) BTA, EGF, IL1β, vWF and FAS;    -   (vi) EGF, IL1β, IL8, TM, and vWF;    -   (vii) dDimer, EGF, IL1β, IL8, VEGF and vWF;    -   (viii) EGF, IL1β, NSE, sTNFR2, VEGF and vWF;    -   (ix) EGF, IL2, TM, sTNFR2, VEGF and CK18;    -   (x) EGF, IL1α, MMP9, MMP9NGAL, NSE, VEGF and vWF;    -   (xi) EGF, IL1β, NGAL, NSE, sTNFR1, VEGF and vWF;    -   (xii) d-Dimer, EGF, IL1α, IL8, NSE, vWF and FAS;    -   (xiii) d-Dimer, EGF, IL1α, IL8 and NGAL;    -   (xiv) IL1α, IL2, IL8, NGAL and sTNFR1;    -   (xv) IL1α, IL10, NGAL, NSE and TNFα;    -   (xvi) d-Dimer, IL2, IL10, MMP9NGAL, NGAL and sTNFR1;    -   (xvii) EGF, FPSA, IL10, NGAL, TNFα and TPSA;    -   (xviii) CEA, IL1α, IL4, IL8, IL10 and NGAL;    -   (xix) EGF, CRP, IL10, MMP9NGAL, NGAL, TM and VEGF;    -   (xx) CEA, CRP, IL10, MMP9NGAL, NGAL, TM and TNFα;    -   (xxi) CEA, d-Dimer, IL2, IL8, IL10, IFNγ and NSE;    -   (xxii) IL4, IFNγ, MCP1, MMP9NGAL and TM;    -   (xxiii) IL1α, IL4, IFNγ, MCP1 and MMP9NGAL;    -   (xxiv) EGF, IL1α, IL4, MCP1, MMP9NGAL;    -   (xxv) dDimer, IL1α, IL4, IL10, MMP9NGAL and sTNFR1;    -   (xxvi) IL4, IL10, MMP9NGAL, TM, sTNFR1 and TNFα;    -   (xxvii) IL1β, IL4, IL8, MCP1, MMP9NGAL and TNFα;    -   (xxviii) IL1α, IL1β, IL2, IL4, IL10, MMP9NGAL and TNFα    -   (xxix) d-Dimer, IL1α, IL4, IFNγ, MCP1, MMP9NGAL and TM; and    -   (xxx) d-Dimer, EGF, IL1α, IL4, IL10, IFNγ, and MMP9NGAL.

Embodiment 94

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, urinary EGF, plasma IL8 and urinary CK18;    -   (ii) serum CEA, plasma IL8, serum NGAL and serum TM;    -   (iii) serum CEA, plasma IL8, serum NGAL and plasma NSE;    -   (iv) BTA, MMP9NGAL, TM, sTNFR2 and VEGF;    -   (v) BTA, IL4, MMP9, NSE and FAS;    -   (vi) BTA, MMP9NGAL, TNFα, sTNFR2 and VEGF;    -   (vii) BTA, MCP1, MMP9, sTNFR2, vWF and FAS;    -   (viii) d-Dimer, IL6, IL8, NGAL, NSE and TNFα;    -   (ix) BTA, IL6, MCP1, TNFα, sTNFR2 and FAS;    -   (x) EGF, CRP, IL8, NGAL, NSE, TM and HA;    -   (xi) BTA, EGF, IL8, MCP1, NGAL, NSE, sTNFR1;    -   (xii) BTA, IL4, MCP1, TM, sTNFR2, vWF and FAS;    -   (xiii) CEA, EGF, IL4, NGAL and TNFα;    -   (xiv) CEA, EGF, IL8, NGAL and TPSA;    -   (xv) CEA, IL8, MCP1, NGAL and TPSA;    -   (xvi) CEA, IL6, IL8, MMP9NGAL, NGAL and VEGF;    -   (xvii) CEA, d-Dimer, CRP, MMP9NGAL, NGAL and NSE;    -   (xviii) CEA, CRP, IL2, MMP9NGAL, NGAL and TM;    -   (xix) CEA, EGF, CRP, IL4, IL8, NGAL and NSE;    -   (xx) CEA, IL6, IL8, IFNγ, NGAL, TM and VEGF;    -   (xxi) CEA, FPSA, CRP, IL4, MMP9NGAL, NGAL and TM;    -   (xxii) IL1α, MMP9NGAL, NSE, sTNFR1 and VEGF;    -   (xxiii) IFNγ, MCP1, MMP9NGAL, NGAL and NSE;    -   (xxiv) IFNγ, MMP9NGAL, NGAL, NSE and TNFα;    -   (xxv) IL6, IFNγ, MMP9NGAL, NGAL, NSE and TNFα;    -   (xxvi) d-Dimer, IL1α, IL4, MMP9NGAL, NSE and VEGF;    -   (xxvii) d-Dimer, EGF, IL1α, IL8, MMP9NGAL and NSE;    -   (xxviii) d-Dimer, EGF, IL1α, IFNγ, MMP9NGAL, TNFα and VEGF;    -   (xxix) EGF, IL1α, IL2, MMP9NGAL, NGAL, NSE and TM; and    -   (xxx) IL1α, IFNγ, MMP9NGAL, NGAL, NSE, TM and TNFα.

Embodiment 95

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum IL2, serum MMP9NGAL, serum NGAL and plasma sTNFR1;    -   (ii) urinary MMP9NGAL, serum NGAL, plasma NGAL and urinary vWF;    -   (iii) serum CEA, serum d-Dimer, plasma d-Dimer and serum IFNγ;    -   (iv) BTA, IL1β, VEGF, vWF and HA;    -   (v) d-Dimer, IL1α, NSE, vWF and HA;    -   (vi) BTA, d-Dimer, IL1β, vWF and HA;    -   (vii) BTA, IL1β, IL4, VEGF, vWF and HA;    -   (viii) BTA, IL1β, IL8, sTNFR2, vWF and HA;    -   (ix) BTA, EGF, IL1α, NSE, vWF and HA;    -   (x) d-Dimer, CRP, IL1α, IL2, NSE, vWF and HA;    -   (xi) BTA, IL1α, IL8, MMP9NGAL, vWF, HA and CK18;    -   (xii) d-Dimer, IL1α, MCP1, NSE, TNFα, vWF and HA;    -   (xiii) CEA, d-Dimer, IL4, NGAL and TM;    -   (xiv) IL1α, MMP9NGAL, NGAL, sTNFR1 and TNFα;    -   (xv) IL2, MMP9NGAL, NGAL, sTNFR1 and VEGF;    -   (xvi) CEA, d-Dimer, IL1α, NGAL, NSE and TM;    -   (xvii) CEA, EGF, IL1α, MMP9NGAL, NGAL and TPSA;    -   (xviii) CEA, d-Dimer, CRP, IL1β, NGAL and TM;    -   (xix) CEA, d-Dimer, FPSA, CRP, IL10, NGAL and TM;    -   (xx) CEA, d-Dimer, CRP, NGAL, NSE, TM and TPSA;    -   (xxi) d-Dimer, IL1α, IL8, IFNγ, MMP9NGAL, NGAL and TM;    -   (xxii) CRP, IL1α, MMP9NGAL, TM and VEGF;    -   (xxiii) CRP, IL1α, IL1β, MMP9NGAL and NGAL;    -   (xxiv) CRP, IL1α, IL4, MMP9NGAL and TM;    -   (xxv) CRP, IL1α, IL2, IL4, MMP9NGAL and TM;    -   (xxvi) EGF, CRP, IL1α, IL1β, MMP9NGAL and VEGF;    -   (xxvii) EGF, IL1α, IL6, MMP9NGAL, TM and TNFα;    -   (xxviii) CRP, IL1α, IL10, MMP9NGAL, TM, TNFα and VEGF;    -   (xxix) IL1α, IL6, IL10, MMP9NGAL, TM, TNFα and VEGF; and    -   (xxx) CRP, IL1α, IL4, IL6, MMP9NGAL, TM and TNFα.

Embodiment 96

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, urinary EGF, serum IL1α and urinary VEGF;    -   (ii) serum CEA, urinary CRP, serum IL1α and urinary VEGF; and    -   (iii) serum CEA, serum-IL1α, plasma IFNγ and urinary VEGF.    -   (iv) EGF, IL2, HA, FAS and CK18;    -   (v) EGF, IL2, MMP9NGAL, HA and CK18;    -   (vi) EGF, vWF, HA, FAS and CK18;    -   (vii) EGF, IL2, IL8, MMP9, HA and CK18;    -   (viii) BTA, EGF, IL1β, IL8, HA and CK18;    -   (ix) d-Dimer, EGF, NSE, vWF, HA and CK18;    -   (x) EGF, CRP, IL1β, IL2, IL8, HA and CK18;    -   (xi) EGF, IL1β, IL4, IL8, vWF, HA and CK18;    -   (xii) EGF, IL1β, IL6, IL8, MMP9, HA and CK18;    -   (xiii) CEA, IL1α, IL4, TM and TNFα;    -   (xiv) CEA, IL1α, IL2, IL4 and IL8;    -   (xv) CEA, IL1α, IL1β, IL4 and VEGF;    -   (xvi) CEA, IL1α, IL4, IL8, MMP9NGAL and sTNFR1;    -   (xvii) CEA, IL1α, IL2, IL4, NSE and sTNFR1;    -   (xviii) CEA, EGF, IL1α, IL4, IL8 and TM;    -   (xix) CEA, IL1α, IL2, IL4, IL8, IFNγ and MMP9NGAL;    -   (xx) CEA, EGF, FPSA, IL1α, IL4, IL8 and VEGF;    -   (xxi) CEA, IL1α, IL2, IL8, IFNγ, MCP1 and sTNFR1;    -   (xxii) d-Dimer, IL8, IL10, NSE and VEGF;    -   (xxiii) d-Dimer, IL8, MMP9NGAL, TNFα and VEGF;    -   (xxiv) EGF, IL8, IL10, MMP9NGAL and sTNFR1;    -   (xxv) EGF, CRP, IL6, IL8, IL10 and sTNFR1;    -   (xxvi) CRP, IL6, IL8, IL10, IFNγ and sTNFR1;    -   (xxvii) d-Dimer, IL4, IL8, MMP9NGAL, NGAL and TNFα;    -   (xxviii) CRP, IL4, IL6, IL8, IL10, MMP9NGAL and TNFα;    -   (xxix) EGF, CRP, IL1β, IL8, IFNγ, NGAL and sTNFR1; and    -   (xxx) d-Dimer, EGF, CRP, IL8, IL10, IFNγ and MMP9NGAL.

Embodiment 97

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) urinary EGF, urinary IL1α, serum IL10 and urinary vWF;    -   (ii) urinary EGF, plasma IL10, urinary VEGF and urinary vWF;    -   (iii) serum sTNFR1, plasma sTNFR1, serum TNFα and urinary vWF;    -   (iv) CRP, IL2, IL8, sTNFR2 and vWF;    -   (v) EGF, IL8, NSE, TNFα and vWF;    -   (vi) BTA, EGF, IL4, vWF and HA;    -   (vii) BTA, EGF, IL1β, IL8, VEGF and vWF;    -   (viii) d-Dimer, CRP, IL8, sTNFR2, vWF and CK18;    -   (ix) d-Dimer, EGF, IL2, VEGF, vWF and FAS;    -   (x) CRP, IL1β, IL6, IL8, MMP9, NGAL and vWF;    -   (xi) d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 and vWF;    -   (xii) BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF;    -   (xiii) CEA, NGAL, NSE, TNFα and TPSA;    -   (xiv) CEA, MMP9NGAL, NGAL, TM and TNFα;    -   (xv) CEA, IL1β, NGAL, sTNFR1 and TPSA;    -   (xvi) CEA, IL1β, IL10, NGAL, TM and VEGF;    -   (xvii) CEA, d-Dimer, IL1β, MMP9NGAL, NGAL and TM;    -   (xviii) CEA, EGF, IL1α, IL1β, NGAL and TNFα;    -   (xix) CEA, IL1α, IL1β, IL10, NGAL, sTNFR1 and TNFα;    -   (xx) CEA, IL1α, NGAL, NSE, TM, TNFα and TPSA;    -   (xxi) CEA, IL1β, IL4, IL10, MMP9NGAL, NGAL and TM;    -   (xxii) IL1α, IL1β, IL4, IFNγ and VEGF;    -   (xxiii) EGF, CRP, IL2, IL4 and IL8;    -   (xxiv) EGF, CRP, IL2, IL10 and NGAL;    -   (xxv) EGF, IL6, IL10, IFNγ, MCP1 and MMP9NGAL;    -   (xxvi) d-Dimer, EGF, IL1β, IL4, IL6 and MCP1;    -   (xxvii) EGF, CRP, IL1β, IL2, MMP9NGAL and NGAL;    -   (xxviii) d-Dimer, EGF, CRP, IL2, IL10, MMP9NGAL and TM;    -   (xxix) CRP, IL1α, IL1β, IL4, IL6, IFNγ and sTNFR1; and    -   (xxx) EGF, CRP, IL4, IL6, IL10, IFNγ and MMP9NGAL.

Embodiment 98

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, urinary CRP, urinary NSE and serum TNF;    -   (ii) serum CEA, urinary CRP, serum IL4 and urinary sTNFR1;    -   (iii) urinary Creatinine, serum IL6, plasma MMP9NGAL and urinary        VEGF;    -   (iv) CRP, NGAL, VEGF, HA and CK18;    -   (v) d-Dimer, TNFα, VEGF, HA and CK18;    -   (vi) MMP9, NSE, TM, VEGF and FAS;    -   (vii) EGF, NGAL, VEGF, vWF, HA and CK18;    -   (viii) CRP, IL1β, IL6, sTNFR1, VEGF and vWF;    -   (ix) d-Dimer, EGF, IL4, VEGF, HA and CK18;    -   (x) CRP, IL1β, IL6, IL8, MMP9, NGAL and vWF;    -   (xi) d-Dimer, IL8, MMP9, NSE, TM, sTNFR2 and vWF;    -   (xii) BTA, d-Dimer, EGF, IL4, NGAL, NSE and vWF;    -   (xiii) CEA, d-Dimer, IL4, MMP9NGAL and sTNFR1;    -   (xiv) CEA, EGF, IL10, MMP9NGAL and TNFα;    -   (xv) CEA, d-Dimer, CRP, IL4 and IL10;    -   (xvi) CEA, d-Dimer, CRP, IL4, IL10 and TM;    -   (xvii) CEA, d-Dimer, CRP, IL4, IL6 and MMP9NGAL;    -   (xviii) CEA, d-Dimer, IL2, IL4, IL8 and MMP9NGAL;    -   (xix) CEA, d-Dimer, EGF, IL4, IL8, IL10 and NSE;    -   (xx) CEA, d-Dimer, CRP, IL4, MCP1, MMP9NGAL and TNFα;    -   (xxi) CEA, d-Dimer, CRP, IL4, IL6, TM and TNFα;    -   (xxii) EGF, IL1α, IL8, MMP9NGAL and VEGF;    -   (xxiii) IL1α, IL8, IFNγ, MMP9NGAL and VEGF;    -   (xxiv) CRP, IL1α, IL8, MMP9NGAL and NGAL;    -   (xxv) EGF, CRP, IL1β, IL8, MMP9NGAL and VEGF;    -   (xxvi) CRP, IL1α, IL6, IL8, IL10, MMP9NGAL;    -   (xxvii) EGF, IL1β, IL4, IL8, MMP9NGAL and VEGF;    -   (xxviii) EGF, CRP, IL1α, IL8, MMP9NGAL, TNFα and VEGF;    -   (xxix) EGF, CRP, IL1β, IL8, MMP9NGAL, sTNFR1 and VEGF; and    -   (xxx) d-Dimer, EGF, IL1β, IL6, IL8, MMP9NGAL and VEGF.

Embodiment 99

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) urinary BTA, serum CEA, plasma IL10 and urinary CK18;    -   (ii) urinary BTA, plasma IL6, serum NSE and plasma NSE;    -   (iii) urinary dipstick protein, urinary BTA, plasma IL6 and        serum NGAL;    -   (iv) BTA, IL1α, NGAL, sTNFR1 and vWF;    -   (v) BTA, IL8, MMP9NGAL, VEGF and CK18;    -   (vi) BTA, IL6, MMP9NGAL, NSE and CK18;    -   (vii) BTA, IL2, MMP9NGAL, sTNFR1, TNFα and VEGF;    -   (viii) BTA, IL2, MMP9NGAL, NGAL, TNFα and CK18;    -   (ix) BTA, IL2, MMP9NGAL, NSE, VEGF and CK18;    -   (x) BTA, IL2, MMP9NGAL, NGAL, sTNFR1, TNFα and VEGF;    -   (xi) BTA, IL2, MMP9NGAL, TM, sTNFR1, vWF and FAS;    -   (xii) BTA, IL2, MMP9NGAL, sTNFR1, VEGF, vWF and CK18;    -   (xiii) CEA, IL1α, NGAL, NSE and TPSA;    -   (xiv) IL1α, MMP9NGAL, NGAL, TPSA and VEGF;    -   (xv) CEA, IL1α, IL10, NGAL and VEGF;    -   (xvi) CEA, IL10, MMP9NGAL, NGAL, TNFα and VEGF;    -   (xvii) IL1α, IL10, MMP9NGAL, NGAL, NSE and VEGF;    -   (xviii) CRP, IL10, MMP9NGAL, NGAL, TPSA and VEGF;    -   (xix) CEA, CRP, IL1β, IL2, TM, sTNFR1 and TPSA;    -   (xx) CRP, IL1β, IL2, IL6, MMP9NGAL, NGAL and TNFα;    -   (xxi) CRP, IL1β, IL2, MMP9NGAL, NGAL, NSE and TNFα;    -   (xxii) IL1α, IL6, IL8, MMP9NGAL and NSE;    -   (xxiii) IL6, IFNγ, MMP9NGAL, NSE and sTNFR1;    -   (xxiv) IL1α, IL1β, IL8, IL10 and MMP9NGAL;    -   (xxv) IL6, IL8, IFNγ, MMP9NGAL, NGAL and NSE;    -   (xxvi) IL1α, IL6, MMP9NGAL, NSE, TM and TNFα;    -   (xxvii) d-Dimer, IL4, IL8, IFNγ, MMP9NGAL and VEGF;    -   (xxviii) IL1α, IL8, IL10, MCP1, MMP9NGAL, NSE and TM;    -   (xxix) d-Dimer, IL2, IL6, IL8, MMP9NGAL, TM and sTNFR1; and    -   (xxx) IL1α, IL2, IL6, IL8, MCP1, MMP9NGAL and NSE.

Embodiment 100

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, plasma IL8, serum TNFα and urinary FAS;    -   (ii) urinary EGF, serum EGF, serum FPSA and serum IL4;    -   (iii) urinary EGF, urinary CRP, urinary IL4 and urinary NSE;    -   (iv) EGF, CRP, IL4, TM and vWF;    -   (v) BTA, d-Dimer, EGF, CRP and IL4;    -   (vi) EGF, CRP, IL4, IL6 and vWF;    -   (vii) d-Dimer, EGF, CRP, IL4, sTNFR1 and vWF;    -   (viii) d-Dimer, EGF, CRP, IL4, sTNFR1 and sTNFR2;    -   (ix) EGF, IL2, IL4, sTNFR2, VEGF and vWF;    -   (x) EGF, CRP, IL4, MCP1, VEGF, FAS and CK18;    -   (xi) d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and vWF;    -   (xii) d-Dimer, EGF, CRP, IL4, IL6, sTNFR2 and CK18;    -   (xiii) CEA, EGF, CRP, IL4 and IFNγ;    -   (xiv) d-Dimer, FPSA, IL6, IFNγ and NGAL;    -   (xv) IL1α, IL4, MMP9NGAL, NGAL and TM;    -   (xvi) IL4, MMP9NGAL, NGAL, NSE, sTNFR1 and TPSA;    -   (xvii) CEA, EGF, FPSA, IL4, NSE and sTNFR1;    -   (xviii) CEA, EGF, FPSA, IL4, MCP1 and VEGF;    -   (xix) FPSA, IL2, IL4, IL6, MMP9NGAL, NGAL and sTNFR1;    -   (xx) CEA, EGF, FPSA, CRP, IL4, IL6 and MMP9NGAL;    -   (xxi) d-Dimer, IL1β, IL4, IL8, MCP1, NGAL and TM;    -   (xxii) d-Dimer, IL1β, IL8, MMP9NGAL and TM;    -   (xxiii) d-Dimer, IL8, TM, TNFα and VEGF;    -   (xxiv) IL2, IL8, MMP9NGAL, TM and TNFα;    -   (xxv) d-Dimer, IL8, MMP9NGAL, NSE, TM and TNFα;    -   (xxvi) d-Dimer, IL2, IL8, MMP9NGAL, NSE and TNFα;    -   (xxvii) d-Dimer, IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (xxviii) d-Dimer, IL1α, IL8, MMP9NGAL, TM, TNFα and VEGF;    -   (xxix) d-Dimer, CRP, IL2, IL6, IL8, MMP9NGAL and TNFα; and    -   (xxx) d-Dimer, IL1α, IL1β, IL8, MMP9NGAL, TM and VEGF.

Embodiment 101

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting

-   -   (i) urinary EGF, urinary IL1β, plasma MMP9NGAL and urinary vWF;    -   (ii) serum CEA, urinary EGF, urinary vWF and urinary CK18;    -   (iii) serum CEA, urinary EGF, plasma NSE and urinary vWF;    -   (iv) EGF, MMP9, sTNFR2, VEGF and vWF;    -   (v) EGF, IL1α, IL4, vWF and FAS;    -   (vi) EGF, IL1α, MMP9, vWF and HA;    -   (vii) d-Dimer, EGF, CRP, IL1α, IL6 and vWF;    -   (viii) EGF, CRP, IL1α, sTNFR, vWF and CK18;    -   (ix) BTA, EGF, CRP, IL1α, vWF and FAS;    -   (x) EGF, IL1α, IL6, NGAL, sTNFR2, vWF and FAS;    -   (xi) EGF, IL1α, IL2, IL6, NGAL, VEGF and vWF;    -   (xii) EGF, IL1α, NGAL, NSE, sTNFR2, vWF and CK18;    -   (xiii) CRP, IL1β, IL6, IL8 and NGAL;    -   (xiv) d-Dimer, IL1β, IL4, IFNγ and NGAL;    -   (xv) CRP, IL1β, IL4, MCP1 and NGAL;    -   (xvi) EGF, CRP, IL1α, IL1β, NGAL and TPSA;    -   (xvii) CEA, CRP, IL1β, IL2, NGAL and NSE;    -   (xviii) CEA, d-Dimer, CRP, IL1α, IL6 and NGAL;    -   (xix) EGF, CRP, IL8, MCP1, MMP9NGAL, NGAL and sTNFR1;    -   (xx) CEA, EGF, CRP, IL1β, MMP9NGAL, NGAL and TM;    -   (xxi) CEA, d-Dimer, IL1α, IL2, IL4, IL10 and NGAL;    -   (xxii) d-Dimer, IL4, MMP9NGAL, NSE and TM;    -   (xxiii) IL1β, IL4, MMP9NGAL, NSE and TNFα;    -   (xxiv) EGF, CRP, IL4, MMP9NGAL and sTNFR1;    -   (xxv) IL1α, IL2, IL4, MMP9NGAL, NSE and TNFα;    -   (xxvi) IL2, IL4, IL6, MMP9NGAL, NSE and TM;    -   (xxvii) CRP, IL1α, IL1β, IL4, MMP9NGAL and TNFα;    -   (xxviii) d-Dimer, IL1β, IL4, MMP9NGAL, NGAL, NSE and VEGF;    -   (xxix) d-Dimer, IL1α, IL2, MMP9NGAL, NSE, sTNFR and TNFα; and    -   (xxx) d-Dimer, CRP, IL1α, IL4, IL10, NSE and sTNFR.

Embodiment 102

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum MMP9NGAL, serum sTNFR1, serum TNFα and urinary VEGF;    -   (ii) serum CEA, urinary EGF, serum IL10 and serum NGAL;    -   (iii) urinary IL6, plasma MMP9NGAL, urinary VEGF and urinary        CK18;    -   (iv) IL2, IL8, NGAL, HA and CK18;    -   (v) IL2, IL4, VEGF, HA and CK18;    -   (vi) IL1β, IL2, IL8, NGAL and CK18;    -   (vii) IL2, IL4, IL8, NGAL, HA and CK18;    -   (viii) BTA, d-Dimer, IL2, IL8, MMP9NGAL and CK18;    -   (ix) IL2, IL4, IL8, sTNFR2, HA and CK18;    -   (x) IL1β, IL2, IL6, IL8, NGAL, NSE and CK18;    -   (xi) IL1α, IL2, IL6, IL8, NGAL, HA and CK18;    -   (xii) BTA, IL1α, IL2, IL8, NGAL, VEGF and CK18;    -   (xiii) CEA, IL1α, IL8, TM and sTNFR1;    -   (xiv) CEA, IL1α, IL6, NGAL and TM;    -   (xv) CEA, IL1α, IL2, TM and sTNFR1;    -   (xvi) CEA, IL2, IL8, NSE, TM and sTNFR1;    -   (xvii) CEA, IL10, MMP9NGAL, NSE, TM and sTNFR1;    -   (xviii) CEA, CRP, IL2, IL10, NGAL and TM;    -   (xix) CEA, CRP, IL4, IL6, IL10, sTNFR1 and TPSA;    -   (xx) CEA, d-Dimer, EGF, IL1α, IL10, NSE and sTNFR1;    -   (xxi) CEA, d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1;    -   (xxii) IL1α, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (xxiii) EGF, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (xxiv) IL1α, IL8, IL10, MMP9NGAL and VEGF;    -   (xxv) IL1α, IL1β, IL10, IFNγ, MMP9NGAL and VEGF;    -   (xxvi) EGF, CRP, IL1α, MMP9NGAL, TNFα and VEGF;    -   (xxvii) IL1α, IL6, IL8, IFNγ, MMP9NGAL and sTNFR1;    -   (xxviii) IL1α, IL2, IL8, IFNγ, MMP9NGAL, sTNFR1 and TNFα;    -   (xxix) IL1α, IL2, IL6, IL10, MMP9NGAL, TNFα and VEGF; and    -   (xxx) IL1α, IL4, IL6, IL10, MMP9NGAL, NGAL and VEGF.

Embodiment 103

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, urinary EGF, urinary VEGF and urinary vWF;    -   (ii) urinary EGF, serum IL8, urinary vWF and urinary HA;    -   (iii) serum IL4, plasma IL8, serum MCP1 and urinary VEGF;    -   (iv) BTA, IL2, IL4, MMP9NGAL and VEGF;    -   (v) BTA, IL1α, IL8, NGAL and NSE;    -   (vi) BTA, CRP, IL4, NSE and CK18;    -   (vii) BTA, d-Dimer, CRP, IL4, sTNFR1 and vWF;    -   (viii) IL4, IL8, NGAL, NSE, TM and sTNFR1;    -   (ix) CRP, IL2, IL8, MCP1, MMP9NGAL and TNFα;    -   (x) EGF, IL1α, IL8, MMP9NGAL, NSE, vWF and CK18;    -   (xi) EGF, IL6, IL8, MMP9NGAL, NSE, VEGF and vWF;    -   (xii) CRP, IL1α, IL6, IL8, MMP9NGAL, NSE and VEGF;    -   (xiii) IL2, IL10, NGAL, NSE and VEGF;    -   (xiv) CEA, IL4, IL8, NGAL and TM;    -   (xv) CEA, CRP, NGAL, NSE and sTNFR1;    -   (xvi) d-Dimer, CRP, IL6, IL8, NSE and sTNFR1;    -   (xvii) CEA, IL4, IL10, IFNγ, MCP1 and NGAL;    -   (xviii) FPSA, IL4, IL8, MMP9NGAL, NSE and sTNFR1;    -   (xix) FPSA, IL1β, IL2, IL4, IL8, MMP9NGAL and NGAL;    -   (xx) CEA, d-Dimer, IL8, IL10, IFNγ, NGAL and NSE;    -   (xxi) CEA, EGF, CRP, IL10, MCP1, NGAL and NSE;    -   (xxii) IL1α, IL6, MMP9NGAL, TM and sTNFR1;    -   (xxiii) IL1α, IL1β, IL6, IL8 and TNFα;    -   (xxiv) IL8, MMP9NGAL, NGAL, NSE and TNFα;    -   (xxv) IL1β, IL2, IL8, MMP9NGAL, NGAL and NSE;    -   (xxvi) IL1β, IL8, IL10, MCP1, NGAL and TM;    -   (xxvii) IL8, IFNγ, MMP9NGAL, TM, sTNFR1 and TNFα;    -   (xxviii) IL1β, IL8, IFNγ, MCP1, MMP9NGAL, TM and sTNFR1;    -   (xxix) IL1α, IL4, IL8, IL10, MCP1, TM and sTNFR1; and    -   (xxx) IL1α, IL1β, IL6, IL8, NGAL, NSE and VEGF.

Embodiment 104

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, serum d-Dimer, urinary EGF and serum IL1α;    -   (ii) serum CEA, serum d-Dimer, serum IL6 and serum MCP1;    -   (iii) urinary BTA, serum CEA, urinary TNFα and urinary CK18;    -   (iv) BTA, TM, TNFα, sTNFR2 and vWF;    -   (v) BTA, TM, TNFα, vWF and FAS;    -   (vi) EGF, NSE, TNFα, vWF and HA;    -   (vii) IL6, MCP1, TNFα, vWF, FAS and CK18;    -   (viii) BTA, d-Dimer, CRP, TNFα, vWF and HA;    -   (ix) BTA, IL1α, TNFα, vWF, HA and FAS;    -   (x) BTA, d-Dimer, MMP9NGAL, TM, TNFα, vWF and HA;    -   (xi) IL6, NGAL, sTNFR, TNFα, vWF, FAS and CK18;    -   (xii) BTA, IL1α, IL1β, IL6, NGAL, TNFα and CK18;    -   (xiii) CEA, d-Dimer, NSE, TM and TPSA;    -   (xiv) CEA, EGF, IL10, MCP1 and sTNFR1;    -   (xv) CEA, d-Dimer, CRP, MCP1 and NGAL;    -   (xvi) CEA, d-Dimer, EGF, IL8, IL10 and TM;    -   (xvii) CEA, d-Dimer, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (xviii) CEA, d-Dimer, EGF, IL6, NGAL and TM;    -   (xix) CEA, d-Dimer, IL4, IL10, MCP1, MMP9NGAL and NSE;    -   (xx) CEA, d-Dimer, IFNγ, MCP1, MMP9NGAL, TM and TPSA;    -   (xxi) CEA, d-Dimer, EGF, IL6, IL10, MMP9NGAL and TM;    -   (xxii) IL4, IL6, IFNγ, MMP9NGAL and NGAL;    -   (xxiii) IA1β, IL4, IL10, MMP9NGAL and TM;    -   (xxiv) IL2, IL4, IL6, IFNγ and MMP9NGAL;    -   (xxv) IL2, IL4, IL10, MMP9NGAL, TNFα and VEGF;    -   (xxvi) CRP, IL4, IL10, MMP9NGAL, TNFα and VEGF;    -   (xxvii) IL1α, IL4, IL10, IFNγ, MMP9NGAL and NSE;    -   (xxviii) IL4, IL6, IL10, MMP9NGAL, NGAL, sTNFR1 and VEGF;    -   (xxix) d-Dimer, CRP, IL1α, IL1β, IL2, IL4 and MMP9NGAL; and    -   (xxx) d-Dimer, CRP, IL1β, IL4, IL6, IL10 and MMP9NGAL.

Embodiment 105

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum MCP1, plasma MCP1, serum NGAL and plasma NGAL;    -   (ii) urinary CRP, serum IL2, serum NGAL and plasma NGAL;    -   (iii) urinary Creatinine, serum NGAL, plasma NGAL and plasma        VEGF;    -   (iv) CRP, MCP1, sTNFR2, vWF and FAS;    -   (v) d-Dimer, IL6, MMP9NGAL, NSE and VEGF;    -   (vi) BTA, MCP1, sTNFR2, vWF and FAS;    -   (vii) d-Dimer, IL6, NGAL, NSE, VEGF and HA;    -   (viii) IL1β, IL6, IL8, MMP9NGAL, NSE and VEGF;    -   (ix) BTA, d-Dimer, IL6, NGAL, NSE and VEGF;    -   (x) BTA, CRP, IL1β, IL8, sTNFR2, vWF and FAS;    -   (xi) d-Dimer, IL4, IL6, MMP9, NSE, VEGF and CK18;    -   (xii) BTA, CRP, IL1α, IL2, sTNFR2, vWF and FAS;    -   (xiii) IL6, IL8, NGAL, TPSA and VEGF;    -   (xiv) FPSA, NGAL, TM, TNFα and VEGF;    -   (xv) IL1β, IL2, NGAL, TM and VEGF;    -   (xvi) IL1α, MCP1, MMP9NGAL, NGAL, TM and TNFα;    -   (xvii) CEA, FPSA, IL8, NGAL, TM and VEGF;    -   (xviii) FPSA, IL4, NGAL, NSE, TNFα and VEGF;    -   (xix) FPSA, IL1β, IL10, NGAL, TM, TNFα and VEGF;    -   (xx) CEA, IL1β, IL4, NGAL, TM, TPSA and VEGF;    -   (xxi) FPSA, IL1β, IL4, IL10, NGAL, TM and VEGF;    -   (xxii) IL2, IFNγ, MCP1, MMP9NGAL and TM;    -   (xxiii) IL1α, IL1β, IL6, TNFα and VEGF;    -   (xxiv) IL4, IL6, IFNγ, MCP1 and TNFα;    -   (xxv) d-Dimer, IL2, IL6, MMP9NGAL, TM and TNFα;    -   (xxvi) IL2, IL10, IFNγ, MCP1, MMP9NGAL and TNFα;    -   (xxvii) IL6, MCP1, NGAL, NSE, TM and TNFα;    -   (xxviii) d-Dimer, EGF, IL6, IL10, IFNγ, MCP1 and TNFα;    -   (xxix) d-Dimer, IL10, IFNγ, MCP1, NGAL, sTNFR and VEGF; and    -   (xxx) d-Dimer, IL6, IL8, IL10, NSE, TM and TNFα.

Embodiment 106

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, urinary EGF, urinary HA and urinary CK18;    -   (ii) serum CEA, urinary EGF, urinary IL8 and urinary CK18;    -   (iii) serum CEA, urinary EGF, plasma IL6 and urinary MMP9NGAL;    -   (iv) BTA, CRP, IL2, IL4 and CK18;    -   (v) EGF, IL1β, NGAL, VEGF and CK18;    -   (vi) BTA, IL4, IL8, HA and CK18;    -   (vii) EGF, CRP, IL4, VEGF, HA and CK18;    -   (viii) EGF, IL4, IL6, IL8, vWF and CK18;    -   (ix) BTA, EGF, IL4, IL8, HA and CK18;    -   (x) BTA, EGF, CRP, IL4, sTNFR1, HA and CK18;    -   (xi) EGF, IL1α, IL1β, IL4, sTNFR1, VEGF and CK18;    -   (xii) EGF, CRP, IL4, MMP9NGAL, NGAL, HA and CK18;    -   (xiii) CEA, FPSA, IL10, IFNγ and NGAL;    -   (xiv) CEA, IL1α, IL1β, MMP9NGAL and sTNFR1;    -   (xv) CEA, IL1α, MMP9NGAL, TM and TNFα;    -   (xvi) CEA, IL1α, IL1β, IL6, NGAL and NSE;    -   (xvii) CEA, IL4, IL6, IL8, MMP9NGAL and TNFα;    -   (xviii) CEA, d-Dimer, IL1α, IL4, IL6 and sTNFR1;    -   (xix) CEA, IL1α, IL4, IL6, IL8, TM and sTNFR1;    -   (xx) CEA, IL1α, IL1β, IL4, IL8, MMP9NGAL and VEGF;    -   (xxi) CEA, IL1α, IL4, IL10, MMP9NGAL, TM and TNFα;    -   (xxii) IL1α, IL8, MMP9NGAL, NGAL and sTNFR1;    -   (xxiii) IL1α, IL1β, IL4, IFNγ and psTNFR1;    -   (xxiv) IL1α, IL1β, IL8, TM and psTNFR1;    -   (xxv) d-Dimer, IL1α, IL4, IL10, MMP9NGAL and TNFα;    -   (xxvi) CRP, IL8, IL10, MMP9NGAL, TM and sTNFR1;    -   (xxvii) d-Dimer, IL1α, IL1β, IL4, TM and sTNFR1;    -   (xxviii) IL1β, IL6, IL8, MMP9NGAL, sTNFR1, TNFα and VEGF;    -   (xxix) d-Dimer, IL1α, IL4, IL8, NGAL, TM and sTNFR1; and    -   (xxx) IL1α, IL1β, IL4, IL6, IL8, MMP9NGAL and sTNFR1.

Embodiment 107

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) serum CEA, plasma CRP, urinary IL8 and plasma TNF;    -   (ii) urinary EGF, urinary IL1β, serum IL6 and urinary vWF;    -   (iii) serum CEA, plasma IL1α, urinary NSE and serum NSE;    -   (iv) EGF, IL2, NSE, TM and CK18;    -   (v) EGF, IL6, sTNFR1, HA and CK18;    -   (vi) EGF, NGAL, vWF, HA and CK18;    -   (vii) EGF, IL8, sTNFR2, VEGF, uvWF and HA;    -   (viii) EGF, IL1α, MMP9, NSE, uvWF and HA;    -   (ix) EGF, CRP, IL2, IL4, TM and CK18;    -   (x) EGF, IL1β, IL2, NSE, TM, VEGF and vWF;    -   (xi) EGF, IL1β, MMP9, MMP9NGAL, TNFα, vWF and HA;    -   (xii) EGF, IL2, IL4, NGAL, NSE, TM and CK18;    -   (xiii) CEA, IL8, IL10, NSE and TNFα;    -   (xiv) CEA, IL2, IL8, MMP9NGAL and NSE;    -   (xv) CEA, IL2, IL6, IL10 and NSE;    -   (xvi) CEA, IL1β, IL2, IL8, IL10 and NSE;    -   (xvii) CEA, IL1β, IL2, IL8, NSE and TPSA;    -   (xviii) CEA, CRP, IL10, MMP9NGAL, NGAL and VEGF;    -   (xix) CEA, IL1β, IL2, IL4, IL8, NSE and TNFα;    -   (xx) CEA, EGF, IL4, IL8, IL10, TPSA and VEGF;    -   (xxi) CEA, IL1β, IL2, IL4, IL10, MMP9NGAL and TM;    -   (xxii) CRP, IL1α, IL8, IFNγ, TM;    -   (xxiii) CRP, IL1α, IL8, IFNγ, NGAL;    -   (xxiv) IL1α, IL2, IL8, MCP1, TM;    -   (xxv) EGF, IL1α, IL4, IL8, IFNγ, TM;    -   (xxvi) d-Dimer, IL1α, IL8, IFNγ, MCP1, TM;    -   (xxvii) IL1α, IL8, IFNγ, MCP1, TM, TNFα;    -   (xxviii) IL1α, IL2, IL8, IL10, IFNγ, MCP1, TM;    -   (xxix) IL1α, IL2, IL8, IFNγ, MCP1, MMP9NGAL, TM; and    -   (xxx) EGF, CRP, IL1α, IL4, IL8, IFNγ, TNFα.

Embodiment 108

A solid state device according to embodiments 91 or 92, comprisingantibodies that bind specifically to a panel of biomarkers selected fromthe group consisting of:

-   -   (i) urinary BTA, urinary NGAL, serum NGAL and urinary TNF;    -   (ii) urinary d-Dimer, urinary CRP, urinary NGAL and serum TNF;    -   (iii) serum CEA, urinary CRP, plasma MMP9NGAL and urinary NGAL;    -   (iv) d-Dimer, CRP, IL4, NGAL and sTNFR2;    -   (v) CRP, MMP9NGAL, NGAL, sTNFR2 and VEGF;    -   (vi) BTA, CRP, IL4, NGAL and sTNFR2;    -   (vii) CRP, MCP1, MMP9, NGAL, sTNFR2 and VEGF;    -   (viii) d-Dimer, CRP, IL2, IL4, NGAL and sTNFR;    -   (ix) BTA, CRP, IL2, NGAL, sTNFR2 and vWF;    -   (x) d-Dimer, CRP, IL1α, IL4, MMP9NGAL, TM and CK18;    -   (xi) BTA, EGF, CRP, MMP9, NGAL, vWF and FAS;    -   (xii) BTA, CRP, NGAL, NSE, TM, sTNFR2 and vWF;    -   (xiii) FPSA, IL1α, IL4, IFNγ and NGAL;    -   (xiv) d-Dimer, IL2, IL4, NGAL and TM;    -   (xv) d-Dimer, IL6, NGAL, TM and sTNFR1;    -   (xvi) d-Dimer, IL1β, IL8, NGAL, TM and TNFα;    -   (xvii) CEA, IL4, IL8, NGAL, TNFα and TPSA;    -   (xviii) d-Dimer, FPSA, IL2, IL6, IL8 and NGAL;    -   (xix) FPSA, CRP, IL2, IL6, NGAL, TNFα and VEGF;    -   (xx) CEA, FPSA, CRP, IL6, IL10, NGAL and VEGF;    -   (xxi) d-Dimer, FPSA, IL1β, IFNγ, MMP9NGAL, NGAL and TM;    -   (xxii) d-Dimer, IL4, MCP1, MMP9NGAL and TNFα;    -   (xxiii) EGF, IL1α, IL2, MMP9NGAL and NGAL;    -   (xxiv) d-Dimer, IL4, MCP1, MMP9NGAL and sTNFR1;    -   (xxv) d-Dimer, IL1β, IL4, IL8, IL10 and MMP9NGAL;    -   (xxvi) d-Dimer, EGF, IL8, IL10, MMP9NGAL and TM;    -   (xxvii) d-Dimer, EGF, IFNγ, MMP9NGAL, NSE and VEGF;    -   (xxviii) EGF, IL1α, IL2, IL4, MCP1, MMP9NGAL and NGAL;    -   (xxix) d-Dimer, EGF, CRP, IL8, MMP9NGAL, NSE and VEGF; and    -   (xxx) d-Dimer, EGF, IL1β, IL8, IL10, MMP9NGAL and VEGF.

Embodiment 109

Use of a solid substrate according to embodiment 93 to identify asubject having urothelial cancer, wherein the subject has a history ofsmoking.

Embodiment 110

Use of a solid substrate according to embodiment 94 to identify asubject having urothelial cancer, wherein the subject does not have ahistory of smoking.

Embodiment 111

Use of a solid substrate according to embodiment 95 to identify asubject having urothelial cancer, wherein the subject is 65 years of ageor older.

Embodiment 112

Use of a solid substrate according to embodiment 96 to identify asubject having urothelial cancer, wherein the subject is less than 65years of age.

Embodiment 113

Use of a solid substrate according to embodiment 97 to identify asubject having urothelial cancer, wherein the subject has a history ofanti-hypertensive medication.

Embodiment 114

Use of a solid substrate according to embodiment 98 to identify asubject having urothelial cancer, wherein the subject does not have ahistory of anti-hypertensive medication.

Embodiment 115

Use of a solid substrate according to embodiment 99 to identify asubject having urothelial cancer, wherein the subject has cytologicaldetection of inflammatory cells.

Embodiment 116

Use of a solid substrate according to embodiment 100 to identify asubject having urothelial cancer, wherein the subject does not havecytological detection of inflammatory cells.

Embodiment 117

Use of a solid substrate according to embodiment 101 to identify asubject having urothelial cancer, wherein the subject has a history ofalcohol consumption.

Embodiment 118

Use of a solid substrate according to embodiment 102 to identify asubject having urothelial cancer, wherein the subject does not have ahistory of alcohol consumption.

Embodiment 119

Use of a solid substrate according to embodiment 103 to identify asubject having urothelial cancer, wherein the subject has a history ofexposure to occupational risk or hazardous chemicals.

Embodiment 120

Use of a solid substrate according to embodiment 104 to identify asubject having urothelial cancer, wherein the subject does not have ahistory of exposure to occupational risk or hazardous chemicals.

Embodiment 121

Use of a solid substrate according to embodiment 105 to identify asubject having urothelial cancer, wherein the subject has a history ofanti-cholesterol medication.

Embodiment 122

Use of a solid substrate according to embodiment 106 to identify asubject having urothelial cancer, wherein the subject does not have ahistory of anti-cholesterol medication.

Embodiment 123

Use of a solid substrate according to embodiment 107 to identify asubject having urothelial cancer, wherein the subject has proteinuria.

Embodiment 124

Use of a solid substrate according to embodiment 108 to identify asubject having urothelial cancer, wherein the subject does not haveproteinuria.

Embodiment 125

Use according to any of embodiments 109 to 124 wherein the subject ispatient a presenting with haematuria.

Embodiment 126

Use according to any of embodiments 109 to 124, wherein the urothelialcancer is urothelial carcinoma (UC).

REFERENCES

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The invention claimed is:
 1. A method, comprising: measuring the levelof each biomarker of a panel of protein biomarkers in a urine sampleobtained from a subject having a history of smoking, wherein the panelof biomarkers consists of: urinary epidermal growth factor (EGF),urinary IL6, urinary vascular endothelial growth factor (VEGF) andurinary cytokeratin 18 (CK18).
 2. A method according to claim 1, whereinthe subject is a patient presenting with haematuria.
 3. The methodaccording to claim 1, wherein the urine and urinary biomarker levels arevolume normalized.